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1.  The effect of integrin-specific bioactive coatings on tissue healing and implant osseointegration 
Biomaterials  2008;29(19):2849-2857.
Implant osseointegration, defined as bone apposition and functional fixation, is a requisite for clinical success in orthopaedic and dental applications, many of which are restricted by implant loosening. Modification of implants to present bioactive motifs such as the RGD cell-adhesive sequence from fibronectin (FN) represents a promising approach in regenerative medicine. However, these biomimetic strategies have yielded only marginal enhancements in tissue healing in vivo. In this study, clinical-grade titanium implants were grafted with a non-fouling oligo(ethylene glycol)-substituted polymer coating functionalized with controlled densities of ligands of varying specificity for target integrin receptors. Biomaterials presenting the α5β1-integrin-specific FN fragment FNIII7–10 enhanced osteoblastic differentiation in bone marrow stromal cells compared to unmodified titanium and RGD-presenting surfaces. Importantly, FNIII7–10-functionalized titanium significantly improved functional implant osseointegration compared to RGD-functionalized and unmodified titanium in vivo. This study demonstrates that bioactive coatings that promote integrin binding specificity regulate marrow-derived progenitor osteoblastic differentiation and enhance healing responses and functional integration of biomedical implants. This work identifies an innovative strategy for the rational design of biomaterials for regenerative medicine.
doi:10.1016/j.biomaterials.2008.03.036
PMCID: PMC2397448  PMID: 18406458
2.  Simple application of fibronectin-mimetic coating enhances osseointegration of titanium implants 
Integrin-mediated cell adhesion to biomolecules adsorbed onto biomedical devices regulates device integration and performance. Because of the central role of integrin-fibronectin (FN) interactions in osteoblastic function and bone formation, we evaluated the ability of fibronectin-inspired biomolecular coatings to promote osteoblastic differentiation and implant osseointegration. Notably, these biomolecular coatings relied on physical adsorption of FN-based ligands onto biomedical-grade titanium as a simple, clinically-translatable strategy to functionalize medical implants. Surfaces coated with a recombinant fragment of FN spanning the central cell binding domain enhanced osteoblastic differentiation and mineralization in bone marrow stromal cell cultures and increased implant osseointegration in a rat cortical bone model compared to passively adsorbed RGD peptides, serum proteins, and full-length FN. Differences in biological responses correlated with integrin binding specificity and signaling among surface coatings. This work validates a simple, clinically-translatable, surface biofunctionalization strategy to enhance biomedical device integration.
doi:10.1111/j.1582-4934.2008.00476.x
PMCID: PMC2819599  PMID: 18752639
fibronectin; osseointegration; coating; integrins; biomimetic; implant
3.  Extracellular matrix-mimetic adhesive biomaterials for bone repair 
Limited osseointegration of current orthopaedic biomaterials contributes to the failure of implants such as arthroplasties, bone screws and bone grafts, which present a large socioeconomic cost within the United States. These implant failures underscore the need for biomimetic approaches that modulate host cell-implant material responses to enhance implant osseointegration and bone formation. Bioinspired strategies have included functionalizing implants with ECM proteins or ECM-derived peptides or protein fragments which engage integrins and direct osteoblast adhesion and differentiation. This review discusses 1) bone ECM composition and key integrins implicated in osteogenic differentiation, 2) the use of implants functionalized with ECM-mimetic peptides/protein fragments, and 3) growth-factor derived peptides to promote the mechanical fixation of implants to bone and to enhance bone healing within large defects.
doi:10.1002/jbm.a.32979
PMCID: PMC3059117  PMID: 21105174
4.  UV- Killed Staphylococcus aureus Enhances Adhesion and Differentiation of Osteoblasts on Bone-associated Biomaterials 
Titanium alloys (Ti) are the preferred material for orthopaedic applications. However, very often, these metallic implants loosen over a long period and mandate revision surgery. For implant success, osteoblasts must adhere to the implant surface and deposit a mineralized extracellular matrix. Here, we utilized UV-killed Staphylococcus aureus as a novel osteoconductive coating for Ti surfaces. S. aureus expresses surface adhesins capable of binding to bone and biomaterials directly. Furthermore, interaction of S. aureus with osteoblasts activates growth factor-related pathways that potentiate osteogenesis. While UV-killed S. aureus cells retain their bone-adhesive ability, they do not stimulate significant immune modulator expression. All of the above properties were utilized for a novel implant coating so as to promote osteoblast recruitment and subsequent cell functions on the bone-implant interface. In the present study, osteoblast adhesion, proliferation, and mineralized extracellular matrix synthesis were measured on Ti surfaces coated with fibronectin with and without UV-killed bacteria. Osteoblast adhesion was enhanced on Ti alloy surfaces coated with bacteria compared to uncoated surfaces while cell proliferation was sustained comparably on both surfaces. Osteoblast markers such as collagen, osteocalcin, alkaline phosphatase activity and mineralized nodule formation were increased on Ti alloy coated with bacteria compared to uncoated surfaces.
doi:10.1002/jbm.a.32890
PMCID: PMC2943998  PMID: 20725968
Titanium implant surfaces; Osseointegration; Staphylococcus aureus; Calvarial osteoblasts; Osteoblast differentiation
5.  Surface Contaminants Inhibit Osseointegration in a Novel Murine Model 
Bone  2011;49(5):923-930.
Surface contaminants, such as bacterial debris and manufacturing residues, may remain on orthopaedic implants after sterilization procedures and affect osseointegration. The goals of this study were to develop a murine model of osseointegration in order to determine whether removing surface contaminants enhances osseointegration. To develop the murine model, titanium alloy implants were implanted into a unicortical pilot hole in the mid-diaphysis of the femur and osseointegration was measured over a five week time course. Histology, backscatter scanning electron microscopy and x-ray energy dispersive spectroscopy showed areas of bone in intimate physical contact with the implant, confirming osseointegration. Histomorphometric quantification of bone-to-implant contact and peri-implant bone and biomechanical pullout quantification of ultimate force, stiffness and work to failure increased significantly over time, also demonstrating successful osseointegration. We also found that a rigorous cleaning procedure significantly enhances bone-to-implant contact and biomechanical pullout measures by two-fold compared with implants that were autoclaved, as recommended by the manufacturer. The most likely interpretation of these results is that surface contaminants inhibit osseointegration. The results of this study justify the need for the development of better detection and removal techniques for contaminants on orthopaedic implants and other medical devices.
doi:10.1016/j.bone.2011.07.013
PMCID: PMC3200470  PMID: 21801863
contaminants; osseointegration; murine; histomorphometry; biomechanical testing
6.  Biological Functionalization of Dental Implants with Fibronectin: A Scanning Electron Microscopic Study 
Objectives
Early stages of peri-implant bone formation play an essential role in the osseointegration and long-term success of dental implants. Biological implant surface coatings are an emerging technology to enhance the attachment of the implant to the surrounding bone and stimulate bone regeneration. The purpose of this study was to determine the effect of coating the implant surface with fibronectin on osseointegration.
Material and methods
The experiment was conducted on a total of twelve New Zealand white mature male rabbits, weight between 2.5–4 kg. Twenty four pure titanium implants were used in this study. Each rabbits received two implants, one implant in each tibia; the implant in the right limb was coated with fibronectin (experimental group), whilst on the contralateral side the implants were placed without coating (control group). Six rabbits were sacrificed for Scanning Electron Microscopic evaluation after 4 and 8 week healing periods.
Results
The results of the present study demonstrating the mean gap distance between the bone and implant was greater in the control group compared to fibronection group at both observation periods however, the difference between these two groups was not statistically significant.
Conclusion
Thus, it could be suggested that the biological functionalization of dental implants with fibronectin, may influence the integration or biocompatibility and bonding of the implant to the surrounding bone.
PMCID: PMC4039585  PMID: 24899880
Dental implant; Osseointegration; Biofunctionalization; Extracellular matrix; Fibronectin
7.  Osseointegration of Titanium Prostheses on the Stapes Footplate 
The success of middle ear reconstructive surgery depends on stable coupling between the prosthesis and residual ossicles. To establish a stable fixed point on the stapes footplate for subsequent prosthesis reconstruction, a titanium footplate anchor was coated with osteoinductive substances to induce a controlled osseointegration on the footplate. Various studies have shown that collagen-based matrices with and without bone growth and differentiation factors can induce and enhance bone formation and consequently increase implant stability. The ears of 23 one-year-old Merino sheep (n = 46) were divided into five groups and implanted with a specially designed footplate anchor. The surface of each implant was modified by applying a collagenous matrix (collagen I or II) either with immobilized bone morphogenic protein (BMP-4) or transforming growth factor-ß, respectively, to stimulate osteoblastic activation and differentiation on the stapes footplate with subsequent osseointegration. Polychrome labeling was used to assess new bone formation and remodeling during the study. After study termination on day 84, synchrotron radiation-based computed microtomography and histomorphometry were used to identify bone implant contact. Eight implants showed radiographical and/or histological evidence of integration by newly formed bone. An osseointegration could histologically be proven in two of these eight specimens, and additional ectopic bone formations were seen in another 21 specimens. In all animals, bone turnover on the footplate was proven by polychrome labeling. This study proves the general ability to induce a controlled osseointegration of titanium implants biologically activated with artificial extracellular matrices on their surfaces on the stapes footplate in a mammalian organism.
doi:10.1007/s10162-009-0202-y
PMCID: PMC2862917  PMID: 20066460
tympanoplasty; reconstruction; animal study; growth factors; implant coating
8.  The effects of combined micron-/submicron-scale surface roughness and nanoscale features on cell proliferation and differentiation 
Biomaterials  2011;32(13):3395-3403.
Titanium (Ti) osseointegration is critical for the success of dental and orthopaedic implants. Previous studies have shown that surface roughness at the micro- and submicro-scales promotes osseointegration by enhancing osteoblast differentiation and local factor production. Only relatively recently have the effects of nanoscale roughness on cell response been considered. The aim of the present study was to develop a simple and scalable surface modification treatment that introduces nanoscale features to the surfaces of Ti substrates without greatly affecting other surface features, and to determine the effects of such superimposed nano-features on the differentiation and local factor production of osteoblasts. A simple oxidation treatment was developed for generating controlled nanoscale topographies on Ti surfaces, while retaining the starting micro-/submicro-scale roughness. Such nano-modified surfaces also possessed similar elemental compositions, and exhibited similar contact angles, as the original surfaces, but possessed a different surface crystal structure. MG63 cells were seeded on machined (PT), nano-modified PT (NMPT), sandblasted/acid-etched (SLA), and nano-modified SLA (NMSLA) Ti disks. The results suggested that the introduction of such nanoscale structures in combination with micro-/submicro-scale roughness improves osteoblast differentiation and local factor production, which, in turn, indicates the potential for improved implant osseointegration in vivo.
doi:10.1016/j.biomaterials.2011.01.029
PMCID: PMC3350795  PMID: 21310480
(4 to 6) nanotopography; titanium oxide; surface roughness; titanium; bone; implant; osteoblasts
9.  Effects of Coating a Titanium Alloy with Fibronectin on the Expression of Osteoblast Gene Markers in the MC3T3 Osteoprogenitor Cell Line 
Purpose
A number of environmental and patient-related factors contribute to implant failure. A significant fraction of these failures can be attributed to limited osseointegration resulting from poor bone healing responses. The overall goal of this study was to determine whether surface treatment of a titanium-aluminum-vanadium alloy (Ti-6Al-4V) implant material with a biomimetic protein coating could promote the differentiation of attached osteoblastic cells. The specific aims of the study were to investigate whether osteoprogenitor cells cultured on a rigorously cleaned implant specimen showed a normal pattern of differentiation and whether preadsorbed fibronectin accelerated or enhanced osteoblast differentiation.
Materials and Methods
Ti-6Al-4V disks were rigorously cleaned, passivated in nitric acid, and dry heat–sterilized; some of the disks were then coated with 1 nmol/L fibronectin. MC3T3 osteoprogenitor cells were then cultured on the pretreated disks for several weeks. Quantitative real-time polymerase chain reaction was performed to measure changes over time in the mRNA levels of osteoblast genes.
Results
Fibronectin increased the peak expression of all analyzed osteoblast gene markers. “Early” genes that normally mark the proliferative phase (0 to 10 days) of osteoblastic development showed peak expression within the first 10 days after cell attachment to the titanium alloy. In contrast, “late” genes that normally mark the differentiation (10 to 20 days) and mineralization (20 to 36 days) phases of osteoblastogenesis achieved peak expression only after approximately 3 to 4 weeks of culture.
Conclusions
Osteoprogenitors cultured on a rigorously cleaned Ti-6Al-4V alloy were found to demonstrate a normal pattern of osteoblast differentiation. Preadsorbed fibronectin was observed to stimulate osteoblast differentiation during the mineralization phase of osteoblastogenesis.
PMCID: PMC3810407  PMID: 23057020
coatings; differentiation; fibronectin; metal oxides; osteoblast; real-time polymerase chain reaction
10.  Regulation of Angiogenesis during Osseointegration by Titanium Surface Microstructure and Energy 
Biomaterials  2010;31(18):4909-4917.
Rough titanium (Ti) surface microarchitecture and high surface energy have been shown to increase osteoblast differentiation, and this response occurs through signaling via the α2β1 integrin. However, clinical success of implanted materials is dependent not only upon osseointegration but also on neovascularization in the peri-implant bone. Here we tested the hypothesis that Ti surface microtopography and energy interact via α2β1 signaling to regulate the expression of angiogenic growth factors. Primary human osteoblasts (HOB), MG63 cells and MG63 cells silenced for α2 integrin were cultured on Ti disks with different surface microtopographies and energies. Secreted levels of vascular endothelial growth factor-A (VEGF-A), basic fibroblast growth factor (FGF-2), epidermal growth factor (EGF), and angiopoietin-1 (Ang-1) were measured. VEGF-A increased 170% and 250% in MG63 cultures, and 178% and 435% in HOB cultures on SLA and modSLA substrates, respectively. In MG63 cultures, FGF-2 levels increased 20 and 40-fold while EGF increased 4 and 6-fold on SLA and modSLA surfaces. These factors were undetectable in HOB cultures. Ang-1 levels were unchanged on all surfaces. Media from modSLA MG63 cultures induced more rapid differentiation of endothelial cells and this effect was inhibited by anti-VEGF-A antibodies. Treatment of MG63 cells with 1α,25(OH)2D3 enhanced levels of VEGF-A on SLA and modSLA. Silencing the α2 integrin subunit increased VEGF-A levels and decreased FGF-2 levels. These results show that Ti surface microtopography and energy modulate secretion of angiogenic growth factors by osteoblasts and that this regulation is mediated at least partially via α2β1 integrin signaling.
doi:10.1016/j.biomaterials.2010.02.071
PMCID: PMC2896824  PMID: 20356623
Titanium; microstructure; surface energy; osteoblast; angiogenesis; VEGF
11.  Effects of Structural Properties of Electrospun TiO2 Nano-fiber Meshes on their Osteogenic Potential 
Acta Biomaterialia  2011;8(2):878-885.
Ideal outcomes in the field of tissue engineering and regenerative medicine involve biomaterials that can enhance cell differentiation and production of local factors for natural tissue regeneration without the use of systemic drugs. Biomaterials typically used in tissue engineering applications include polymeric scaffolds that mimic the 3-D structural environment of the native tissue, but these are often functionalized with proteins or small peptides to improve their biological performance. For bone applications, titanium (Ti) implants, or more appropriately the titania (TiO2) passive oxide layer formed on their surface, have been shown to enhance osteoblast differentiation in vitro and to promote osseointegration in vivo. In this study we evaluated the effect on osteoblast differentiation of pure TiO2 nano-fiber meshes with different surface micro-roughness and nano-fiber diameters, prepared by the electrospinning method. MG63 cells were seeded on TiO2 meshes, and cell number, differentiation markers and local factor production were analyzed. The results showed that cells grew throughout the entire surfaces and with similar morphology in all groups. Cell number was sensitive to surface micro-roughness, whereas cell differentiation and local factor production was regulated by both surface roughness and nano-fiber diameter. These results indicate that scaffold structural cues alone can be used to drive cell differentiation and create an osteogenic environment without the use of exogenous factors.
doi:10.1016/j.actbio.2011.10.023
PMCID: PMC3309709  PMID: 22075122
nano structures; electrospinning; scaffold; titanium implant; tissue engineering; bone
12.  Hybrid micro/nano-topography of a TiO2 nanotube-coated commercial zirconia femoral knee implant promotes bone cell adhesion in vitro 
Various approaches have been studied to engineer the implant surface to enhance bone in-growth properties, particularly using micro- and nano- topography. In this study, the behavior of osteoblast (bone) cells was analyzed in response to a titanium oxide (TiO2) nanotube-coated commercial zirconia femoral knee implant consisting of a combined surface structure of a micro-roughened surface with the nanotube coating. The osteoblast cells demonstrated high degrees of adhesion and integration into the surface of the nanotube-coated implant material, indicating preferential cell behavior on this surface when compared to the bare implant. The results of this brief study provide sufficient evidence to encourage future studies. The development of such hierarchical micro and nano topographical features, as demonstrated in this work, can provide for insightful designs for advanced bone-inducing material coatings on ceramic orthopedic implant surfaces.
doi:10.1016/j.msec.2013.02.045
PMCID: PMC4038697  PMID: 23623092
TiO2 nanotube; osteoblast; orthopedic implant; zirconia; cell adhesion; osseointegration
13.  Osteoblast Maturation and New Bone Formation in Response to Titanium Implant Surface Features are Reduced with Age 
The surface properties of materials contribute to host cellular response and play a significant role in determining the overall success or failure of an implanted biomaterial. Rough titanium (Ti) surface microtopography and high surface free energy have been shown to enhance osteoblast maturation in vitro and increase bone formation in vivo. While the surface properties of Ti are known to affect osteoblast response, host bone quality also plays a significant role in determining successful osseointegration. One factor affecting host bone quality is patient age. We examined both in vitro and in vivo whether response to Ti surface features was affected by animal age. Calvarial osteoblasts isolated from 1-, 3-, and 11-month-old rats all displayed a reduction in cell number and increases in alkaline phosphatase specific activity and osteocalcin in response to increasing Ti surface microtopography and surface energy. Further, osteoblasts from the three ages examined displayed increased production of osteocalcin and local factors osteoprotegerin, VEGF-A, and active TGF-β1 in response to increasing Ti surface roughness and surface energy. Latent TGF-β1 only increased in cultures of osteoblasts from 1- and 3-month-old rats. Treatment with the systemic osteotropic hormone 1α,25(OH)2D3 further enhanced the response of osteoblasts to Ti surface features for all three age groups. However, osteoblasts derived from 11-month-old animals had a reduced response to 1α,25(OH)2D3 as compared to osteoblasts derived from 1-or 3-month-old animals. These results were confirmed in vivo. Ti implants placed in the femoral intramedullary canal of old (9-month) mice yielded lower bone-to-implant contract and neovascularization in response to Ti surface roughness and energy compared to younger (2-month) mice. These results show that rodent osteoblast maturation in vitro as well as new bone formation in vivo is reduced with age. Whether comparable age differences exist in humans needs to be determined.
doi:10.1002/jbmr.1628
PMCID: PMC3835587  PMID: 22492532
14.  Early bone growth on the surface of titanium implants in rat femur is enhanced by an amorphous diamond coating 
Acta Orthopaedica  2011;82(4):499-503.
Background and purpose
Amorphous diamond (AD) is a durable and compatible biomaterial for joint prostheses. Knowledge regarding bone growth on AD-coated implants and their early-stage osseointegration is poor. We investigated bone growth on AD-coated cementless intramedullary implants implanted in rats. Titanium was chosen as a reference due to its well-known performance.
Materials and methods
We placed AD-coated and non-coated titanium implants (Ra ≈ 0.2 μm) into the femoral bone marrow of 25 rats. The animals were divided in 2 groups according to implant coating and they were killed after 4 or 12 weeks. The osseointegration of the implants was examined from hard tissue specimens by measuring the new bone formation on their surface.
Results
4 weeks after the operation, the thickness of new bone in the AD-coated group was greater than that in the non-coated group (15.3 (SD 7.1) μm vs. 7.6 (SD 6.0) μm). 12 weeks after the operation, the thickness of new bone was similar in the non-coated group and in the AD-coated group.
Interpretation
We conclude that AD coating of femoral implants can enhance bone ongrowth in rats in the acute, early stage after the operation and might be an improvement over earlier coatings.
doi:10.3109/17453674.2011.579522
PMCID: PMC3237044  PMID: 21504369
15.  The Effect of Hydroxyapatite Nanocrystals on Osseointegration of Titanium Implants: An In Vivo Rabbit Study 
Osseointegration is dependent on implant surface characteristics, including surface chemistry and topography. The presence of nanosized calcium phosphates on the implant surface is interesting to investigate since they affect both the nanotopography and surface chemistry, forming a bone mineral resembling surface. In this work, the osseointegration of titanium implants with and without the presence of hydroxyapatite (HA) nanocrystals has been evaluated in vivo. The integration was examined using removal torque measurements and real-time polymerase chain reaction (RT-PCR) analysis. The study was performed using two healing time points, 3 and 12 weeks. The results showed that the torque needed to remove the implants was insignificant between the non- and HA-coated implants, both at weeks 3 and 12. The RT-PCR, however, showed significant differences for osteoblast, osteoclast, and proinflammation markers when HA nanocrystals were present.
doi:10.1155/2014/171305
PMCID: PMC3915854  PMID: 24563651
16.  Bone integration capability of nanopolymorphic crystalline hydroxyapatite coated on titanium implants 
The mechanism by which hydroxyapatite (HA)-coated titanium promotes bone–implant integration is largely unknown. Furthermore, refining the fabrication of nano-structured HA to the level applicable to the mass production process for titanium implants is challenging. This study reports successful creation of nanopolymorphic crystalline HA on microroughened titanium surfaces using a combination of flame spray and low-temperature calcination and tests its biological capability to enhance bone–implant integration. Sandblasted microroughened titanium implants and sandblasted + HA-coated titanium implants were subjected to biomechanical and histomorphometric analyses in a rat model. The HA was 55% crystallized and consisted of nanoscale needle-like architectures developed in various diameters, lengths, and orientations, which resulted in a 70% increase in surface area compared to noncoated microroughened surfaces. The HA was free from impurity contaminants, with a calcium/phosphorus ratio of 1.66 being equivalent to that of stoichiometric HA. As compared to microroughened implants, HA-coated implants increased the strength of bone–implant integration consistently at both early and late stages of healing. HA-coated implants showed an increased percentage of bone–implant contact and bone volume within 50 μm proximity of the implant surface, as well as a remarkably reduced percentage of soft tissue intervention between bone and the implant surface. In contrast, bone volume outside the 50 μm border was lower around HA-coated implants. Thus, this study demonstrated that the addition of pure nanopolymorphic crystalline HA to microroughened titanium not only accelerates but also enhances the level of bone–implant integration and identified the specific tissue morphogenesis parameters modulated by HA coating. In particular, the nanocrystalline HA was proven to be drastic in increasing osteoconductivity and inhibiting soft tissue infiltration, but the effect was limited to the immediate microenvironment surrounding the implant.
doi:10.2147/IJN.S28082
PMCID: PMC3284227  PMID: 22359461
osseointegration; dental and orthopedic implant; nanotechnology; bone–implant integration; HA; calcium phosphate
17.  Cell response to a newly developed Ti-10Ta-10Nb alloy and its sputtered nanoscale coating 
STATEMENT OF PROBLEM
The success of titanium implants is due to osseointegration or the direct contact of the implant surface and bone without a fibrous connective tissue interface.
PURPOSE
The purpose of this study was to evaluate the osteoblast precursor response to titanium - 10 tantalum - 10 niobium (Ti-Ta-Nb) alloy and its sputtered coating.
MATERIAL AND METHODS
Ti-Ta-Nb coatings were sputtered onto the Ti-Ta-Nb disks. Ti6-Al-4V alloy disks were used as controls. An osteoblast precursor cell line, were used to evaluate the cell responses to the 3 groups. Cell attachment was measured using coulter counter and the cell morphology during attachment period was observed using fluorescent microscopy. Cell culture was performed at 4, 8, 12 and 16 days.
RESULTS
The sputtered Ti-Ta-Nb coatings consisted of dense nanoscale grains in the range of 30 to 100 nm with alpha-Ti crystal structure. The Ti-Ta-Nb disks and its sputtered nanoscale coatings exhibited greater hydrophilicity and rougher surfaces compared to the Ti-6Al-4V disks. The sputtered nanoscale Ti-Ta-Nb coatings exhibited significantly greater cell attachment compared to Ti-6Al-4V and Ti-Ta-Nb disks. Nanoscale Ti-Ta-Nb coatings exhibited significantly greater ALP specific activity and total protein production compared to the other 2 groups.
CONCLUSIONS
It was concluded that nanoscale Ti-Ta-Nb coatings enhance cell adhesion. In addition, Ti-Ta-Nb alloy and its nanoscale coatings enhanced osteoblast differentiation, but did not support osteoblast precursor proliferation compared to Ti-6Al-4V. These results indicate that the new developed Ti-Ta-Nb alloy and its nanoscale Ti-Ta-Nb coatings may be useful as an implant material.
doi:10.4047/jap.2009.1.1.56
PMCID: PMC2994675  PMID: 21165256
Implant; Ti-Ta-Nb; Cell response; Sputter; Nanoscale; Osteoblast
18.  Coating of Biomaterial Scaffolds with the Collagen-Mimetic Peptide GFOGER for Bone Defect Repair 
Biomaterials  2009;31(9):2574.
Healing large bone defects and non-unions remains a significant clinical problem. Current treatments, consisting of auto- and allografts, are limited by donor supply and morbidity, insufficient bioactivity and risk of infection. Biotherapeutics, including cells, genes and proteins, represent promising alternative therapies, but these strategies are limited by technical roadblocks to biotherapeutic delivery, cell sourcing, high cost, and regulatory hurdles. In the present study, the collagen-mimetic peptide, GFOGER, was used to coat synthetic PCL scaffolds to promote bone formation in critically-sized segmental defects in rats. GFOGER is a synthetic triple helical peptide that binds to the α2β1 integrin receptor involved in osteogenesis. GFOGER coatings passively-adsorbed onto polymeric scaffolds, in the absence of exogenous cells or growth factors, significantly accelerated and increased bone formation in non-healing femoral defects compared to uncoated scaffolds and empty defects. Despite differences in bone volume, no differences in torsional strength were detected after 12 weeks, indicating that bone mass but not bone quality was improved in this model. This work demonstrates a simple, cell/growth factor-free strategy to promote bone formation in challenging, non-healing bone defects. This biomaterial coating strategy represents a cost effective and facile approach translatable into a robust clinical therapy for musculoskeletal applications.
doi:10.1016/j.biomaterials.2009.12.008
PMCID: PMC2813962  PMID: 20056517
biomimetic material; bone regeneration; ECM (extracellular matrix); integrin; peptide; scaffold
19.  Nanotechnology and Dental Implants 
The long-term clinical success of dental implants is related to their early osseointegration. This paper reviews the different steps of the interactions between biological fluids, cells, tissues, and surfaces of implants. Immediately following implantation, implants are in contact with proteins and platelets from blood. The differentiation of mesenchymal stem cells will then condition the peri-implant tissue healing. Direct bone-to-implant contact is desired for a biomechanical anchoring of implants to bone rather than fibrous tissue encapsulation. Surfaces properties such as chemistry and roughness play a determinant role in these biological interactions. Physicochemical features in the nanometer range may ultimately control the adsorption of proteins as well as the adhesion and differentiation of cells. Nanotechnologies are increasingly used for surface modifications of dental implants. Another approach to enhance osseointegration is the application of thin calcium phosphate (CaP) coatings. Bioactive CaP nanocrystals deposited on titanium implants are resorbable and stimulate bone apposition and healing. Future nanometer-controlled surfaces may ultimately direct the nature of peri-implant tissues and improve their clinical success rate.
doi:10.1155/2010/915327
PMCID: PMC3021857  PMID: 21253543
20.  Direct and Indirect Effects of Microstructured Titanium Substrates on the Induction of Mesenchymal Stem Cell Differentiation towards the Osteoblast Lineage 
Biomaterials  2010;31(10):2728.
Microstructured and high surface energy titanium substrates increase osseointegration in vivo. In vitro, osteoblast differentiation is increased, but effects of the surface directly on multipotent mesenchymal stem cells (MSCs) and consequences for MSCs in the peri-implant environment are not known. We evaluated responses of human MSCs to substrate surface properties and examined the underlying mechanisms involved. MSCs exhibited osteoblast characteristics (alkaline phosphatase, RUNX2, and osteocalcin) when grown on microstructured Ti; this effect was more robust with increased hydrophilicity. Factors produced by osteoblasts grown on microstructured Ti were sufficient to induce co-cultured MSC differentiation to osteoblasts. Silencing studies showed that this was due to signaling via α2β1 integrins in osteoblasts on the substrate surface and paracrine action of secreted Dkk2. Thus, human MSCs are sensitive to substrate properties that induce osteoblastic differentiation; osteoblasts interact with these surface properties via α2β1 and secrete Dkk2, which acts on distal MSCs.
doi:10.1016/j.biomaterials.2009.12.029
PMCID: PMC2821717  PMID: 20053436
21.  Osteogenic activity of titanium surfaces with nanonetwork structures 
Background
Titanium surfaces play an important role in affecting osseointegration of dental implants. Previous studies have shown that the titania nanotube promotes osseointegration by enhancing osteogenic differentiation. Only relatively recently have the effects of titanium surfaces with other nanostructures on osteogenic differentiation been investigated.
Methods
In this study, we used NaOH solutions with concentrations of 2.5, 5.0, 7.5, 10.0, and 12.5 M to develop a simple and useful titanium surface modification that introduces the nanonetwork structures with titania nanosheet (TNS) nanofeatures to the surface of titanium disks. The effects of such a modified nanonetwork structure, with different alkaline concentrations on the osteogenic differentiation of rat bone marrow mesenchymal stem cells (BMMSCs), were evaluated.
Results
The nanonetwork structures with TNS nanofeatures induced by alkali etching markedly enhanced BMMSC functions of cell adhesion and osteogenesis-related gene expression, and other cell behaviors such as proliferation, alkaline phosphatase activity, extracellular matrix deposition, and mineralization were also significantly increased. These effects were most pronounced when the concentration of NaOH was 10.0 M.
Conclusion
The results suggest that nanonetwork structures with TNS nanofeatures improved BMMSC proliferation and induced BMMSC osteogenic differentiation. In addition, the surfaces formed with 10.0 M NaOH suggest the potential to improve the clinical performance of dental implants.
doi:10.2147/IJN.S58502
PMCID: PMC3983010  PMID: 24741311
nanotopography; osseointegration; surface modification; bone marrow mesenchymal stem cells
22.  Non-mulberry silk fibroin influence osteogenesis and osteoblast-macrophage cross talk on titanium based surface 
Scientific Reports  2014;4:4745.
The titanium and its alloys are used as orthopedic dental implants due to their mechanical and bio-inert properties. The bare metal implants are not the ultimate answer for better osteogenesis and implant integration. Physical and chemical modifications are carried out to achieve the goal of improved adhesion and differentiation of the osteoblast. In this work, the silk fibroins from both mulberry and non-mulberry sources are used for surface modification. Silk fibroins are immobilized on titanium surface to facilitate the initial cell adhesion followed by improved cell spreading and better mineralization in order to achieve enhanced osseointegration. The immunological responses along with the effect of cytokines on osteoblast adhesion and function are investigated. The non-mulberry fibroin performs better in the context of the cell adherence and differentiation, which lead to better mineralization. The results indicate that the silk fibroin from non-mulberry source can be used for better osteogenesis on orthopedic implants.
doi:10.1038/srep04745
PMCID: PMC3994497  PMID: 24752225
23.  Titanium nanotubes stimulate osteoblast differentiation of stem cells from pulp and adipose tissue 
Dental Research Journal  2012;9(Suppl 2):S169-S174.
Background:
Titanium is the gold standard among materials used for prosthetic devices because of its good mechanical and chemical properties. When exposed to oxygen, titanium becomes an oxide, anatase that is biocompatible and able to induce osseointegration.
Materials and Methods:
In this study we compared the expression profiling of stem cells cultivated on two types of surface: Pure titanium disk and nanotube titanium disk in order to detect if nanotube titanium instead (NTD) surface stimulates stem cells towards osteoblast differentiation.
Results:
Stem cells cultivated on nanotube titanium disks showed the upregulation of bone-related genes RUNX2, FOSL1 and SPP1.
Conclusions:
Results demonstrated that nanotube titanium disk surface is more osteo-induced surface compared to titanium disk, promoting the differentiation of mesenchymal stem cells in osteoblasts.
doi:10.4103/1735-3327.109745
PMCID: PMC3692168  PMID: 23814578
Gene expression; nanotubes; osteoblasts; stem cells; titanium disks
24.  Use of polyelectrolyte thin films to modulate Osteoblast response to microstructured titanium surfaces 
Biomaterials  2012;33(21):5267-5277.
The microstructure and wettability of titanium (Ti) surfaces directly impact osteoblast differentiation in vitro and in vivo. These surface properties are important variables that control initial interactions of an implant with the physiological environment, potentially affecting osseointegration. The objective of this study was to use polyelectrolyte thin films to investigate how surface chemistry modulates response of human MG63 osteoblast-like cells to surface microstructure. Three polyelectrolytes, chitosan, poly(l-glutamic acid), and poly(l-lysine), were used to coat Ti substrates with two different microtopographies (PT, Sa = 0.37 µm and SLA, Sa = 2.54 µm). The polyelectrolyte coatings significantly increased wettability of PT and SLA without altering micron-scale roughness or morphology of the surface. Enhanced wettability of all coated PT surfaces was correlated with increased cell numbers whereas cell number was reduced on coated SLA surfaces. Alkaline phosphatase specific activity was increased on coated SLA surfaces than on uncoated SLA whereas no differences in enzyme activity were seen on coated PT compared to uncoated PT. Culture on chitosan-coated SLA enhanced osteocalcin and osteoprotegerin production. Integrin expression on smooth surfaces was sensitive to surface chemistry, but microtexture was the dominant variable in modulating integrin expression on SLA. These results suggest that surface wettability achieved using different thin films has a major role in regulating osteoblast response to Ti, but this is dependent on the microtexture of the substrate.
doi:10.1016/j.biomaterials.2012.03.074
PMCID: PMC3618464  PMID: 22541354
Wettability; Titanium; Surface roughness; Osteoblast
25.  The Effects of Different Wavelength UV Photofunctionalization on Micro-Arc Oxidized Titanium 
PLoS ONE  2013;8(7):e68086.
Many challenges exist in improving early osseointegration, one of the most critical factors in the long-term clinical success of dental implants. Recently, ultraviolet (UV) light-mediated photofunctionalization of titanium as a new potential surface treatment has aroused great interest. This study examines the bioactivity of titanium surfaces treated with UV light of different wavelengths and the underlying associated mechanism. Micro-arc oxidation (MAO) titanium samples were pretreated with UVA light (peak wavelength of 360 nm) or UVC light (peak wavelength of 250 nm) for up to 24 h. UVC treatment promoted the attachment, spread, proliferation and differentiation of MG-63 osteoblast-like cells on the titanium surface, as well as the capacity for apatite formation in simulated body fluid (SBF). These biological influences were not observed after UVA treatment, apart from a weaker effect on apatite formation. The enhanced bioactivity was substantially correlated with the amount of Ti-OH groups, which play an important role in improving the hydrophilicity, along with the removal of hydrocarbons on the titanium surface. Our results showed that both UVA and UVC irradiation altered the chemical properties of the titanium surface without sacrificing its excellent physical characteristics, suggesting that this technology has extensive potential applications and merits further investigation.
doi:10.1371/journal.pone.0068086
PMCID: PMC3702557  PMID: 23861853

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