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1.  Molecular plasma deposition: biologically inspired nanohydroxyapatite coatings on anodized nanotubular titanium for improving osteoblast density 
In order to begin to prepare a novel orthopedic implant that mimics the natural bone environment, the objective of this in vitro study was to synthesize nanocrystalline hydroxyapatite (NHA) and coat it on titanium (Ti) using molecular plasma deposition (MPD). NHA was synthesized through a wet chemical process followed by a hydrothermal treatment. NHA and micron sized hydroxyapatite (MHA) were prepared by processing NHA coatings at 500°C and 900°C, respectively. The coatings were characterized before and after sintering using scanning electron microscopy, atomic force microscopy, and X-ray diffraction. The results revealed that the post-MPD heat treatment of up to 500°C effectively restored the structural and topographical integrity of NHA. In order to determine the in vitro biological responses of the MPD-coated surfaces, the attachment and spreading of osteoblasts (bone-forming cells) on the uncoated, NHA-coated, and MHA-coated anodized Ti were investigated. Most importantly, the NHA-coated substrates supported a larger number of adherent cells than the MHA-coated and uncoated substrates. The morphology of these cells was assessed by scanning electron microscopy and the observed shapes were different for each substrate type. The present results are the first reports using MPD in the framework of hydroxyapatite coatings on Ti to enhance osteoblast responses and encourage further studies on MPD-based hydroxyapatite coatings on Ti for improved orthopedic applications.
doi:10.2147/IJN.S65308
PMCID: PMC4298345  PMID: 25609958
hydroxyapatite; anodization; nanotechnology
2.  Formulation and evaluation of a topical niosomal gel containing a combination of benzoyl peroxide and tretinoin for antiacne activity 
A skin disease, like acne, is very common and normally happens to everyone at least once in their lifetime. The structure of the stratum corneum is often compared with a brick wall, with corneocytes surrounded by the mortar of the intercellular lipid lamellae. One of the best options for successful drug delivery to the affected area of skin is the use of elastic vesicles (niosomes) which can be transported through the skin through channel-like structures. In this study, a combination of tretinoin (keratolytic agent) and benzoyl peroxide (BPO) (a potent antibacterial) was given by using niosomes as promising carriers for the effective treatment of acne by acting on a pathogenic site. In this section, niosomal gel formulation encapsulated drugs have been evaluated for in vitro, ex vivo, and in vivo, for their predetermined characteristics; and finally the stability of the niosome gel was tested at different temperature conditions for understanding of the storage conditions required for maintaining the quality of formulation attributes. The prepared niosome was found to be in the range of 531 nm with a zeta potential of −43 mV; the entrapment efficiencies of tretinoin (TRA) and BPO niosomes were found to be 96.25%±0.56% and 98.75%±1.25%, respectively. The permeated amount of TRA and BPO from the niosomal gel after 24 hours was calculated as 6.25±0.14 μg/cm2 and 5.04±0.014 μg/cm2, respectively. A comparative drug retention study in Wistar rat skin using cream, an alcoholic solution, and a niosomal gel showed 11.54 μg, 2.68 μg, and 15.54 μg amounts of TRA and 68.85 μg, 59.98 μg, and 143.78 μg amounts of BPO were retained in the layers of skin, respectively. In vivo studies of the niosomal gel and antiacne cream of TRA and BPO showed that the niosomal gel was more efficacious than the antiacne cream because niosomal gels with a 4.16-fold lower dose of BPO provided the same therapeutic index at targeted sites in comparison to the antiacne cream.
doi:10.2147/IJN.S70449
PMCID: PMC4283991  PMID: 25565812
antiacne combination therapy; rabbit ear pinna model; retention efficiency; therapeutic index
3.  Understanding greater cardiomyocyte functions on aligned compared to random carbon nanofibers in PLGA 
Previous studies have demonstrated greater cardiomyocyte density on carbon nanofibers (CNFs) aligned (compared to randomly oriented) in poly(lactic-co-glycolic acid) (PLGA) composites. Although such studies demonstrated a closer mimicking of anisotropic electrical and mechanical properties for such aligned (compared to randomly oriented) CNFs in PLGA composites, the objective of the present in vitro study was to elucidate a deeper mechanistic understanding of how cardiomyocyte densities recognize such materials to respond more favorably. Results showed lower wettability (greater hydrophobicity) of CNFs embedded in PLGA compared to pure PLGA, thus providing evidence of selectively lower wettability in aligned CNF regions. Furthermore, the results correlated these changes in hydrophobicity with increased adsorption of fibronectin, laminin, and vitronectin (all proteins known to increase cardiomyocyte adhesion and functions) on CNFs in PLGA compared to pure PLGA, thus providing evidence of selective initial protein adsorption cues on such CNF regions to promote cardiomyocyte adhesion and growth. Lastly, results of the present in vitro study further confirmed increased cardiomyocyte functions by demonstrating greater expression of important cardiomyocyte biomarkers (such as Troponin-T, Connexin-43, and α-sarcomeric actin) when CNFs were aligned compared to randomly oriented in PLGA. In summary, this study provided evidence that cardiomyocyte functions are improved on CNFs aligned in PLGA compared to randomly oriented in PLGA since CNFs are more hydrophobic than PLGA and attract the adsorption of key proteins (fibronectin, laminin, and vironectin) that are known to promote cardiomyocyte adhesion and expression of important cardiomyocyte functions. Thus, future studies should use this knowledge to further design improved CNF:PLGA composites for numerous cardiovascular applications.
doi:10.2147/IJN.S74173
PMCID: PMC4275055  PMID: 25565806
cardiomyocytes; poly(lactic-co-glycolic acid); carbon nanofibers; aligned; nanotechnology; anisotropy; mechanism; vitronectin; fibronectin; laminin
4.  Similar healthy osteoclast and osteoblast activity on nanocrystalline hydroxyapatite and nanoparticles of tri-calcium phosphate compared to natural bone 
While there have been numerous studies to determine osteoblast (bone forming cell) functions on nanocrystalline compared to micron crystalline ceramics, there have been few studies which have examined osteoclast activity (including tartrate-resistant acid phosphatase, formation of resorption pits, size of resorption pits, and receptor activator of nuclear factor κB [RANK]). This is despite the fact that osteoclasts are an important part of maintaining healthy bone since they resorb bone during the bone remodeling process. Moreover, while it is now well documented that bone formation is enhanced on nanoceramics compared to micron ceramics, some have pondered whether osteoblast functions (such as osteoprotegerin and RANK ligand [RANKL]) are normal (ie, non-diseased) on such materials compared to natural bone. For these reasons, the objective of the present in vitro study was to determine various functions of osteoclasts and osteoblasts on nanocrystalline and micron crystalline hydroxyapatite as well as tri-calcium phosphate materials and compare such results to cortical and cancellous bone. Results showed for the first time similar osteoclast activity (including tartrate-resistant acid phosphatase, formation of resorption pits, size of resorption pits, and RANK) and osteoblast activity (osteoprotegerin and RANKL) on nanocrystalline hydroxyapatite compared to natural bone, whereas osteoclast and osteoblast functions on micron crystalline versions of these ceramics were much different than natural bone. In this manner, this study provides additional evidence that nanocrystalline calcium phosphates can serve as suitable synthetic analogs to natural bone to improve numerous orthopedic applications. It also provides the first data of healthy osteoclast and osteoblast functions on nanocrystalline calcium phosphates compared to natural bone.
doi:10.2147/IJN.S66852
PMCID: PMC4260657  PMID: 25506216
hydroxyapatite; osteoclasts; tri-calcium phosphate; nanocrystalline; nanophase; orthopedics
5.  Greater cardiomyocyte density on aligned compared with random carbon nanofibers in polymer composites 
Carbon nanofibers (CNFs) randomly embedded in poly (lactic-co-glycolic-acid) (PLGA) composites have recently been shown to promote cardiomyocyte growth when compared with conventional PLGA without CNFs. It was shown then that PLGA:CNF composites were conductive and that conductivity increased as greater amounts of CNFs were added to pure PLGA. Moreover, tensile tests showed that addition of CNFs increased the tensile strength of the PLGA composite to mimic that of natural heart tissue. Most importantly, throughout all cytocompatibility experiments, cardiomyocytes were viable and expressed important biomarkers that were greatest on 50:50 wt% CNF:PLGA composites. The increased selective adsorption of fibronectin and vitronectin (critical proteins that mediate cardiomyocyte function) onto such composites proved to be the mechanism of action. However, the natural myocardium is anisotropic in terms of mechanical and electrical properties, which was not emulated in these prior PLGA:CNF composites. Thus, the aim of this in vitro study was to create and characterize CNFs aligned in PLGA composites (at 50:50 wt%, including their mechanical and electrical properties and cardiomyocyte density), comparing such results with randomly oriented CNFs in PLGA. Specifically, CNFs were added to soluble biodegradable PLGA (50:50 PGA:PLA weight ratio) and aligned by applying a voltage and then allowing the polymer to cure. CNF surface micron patterns (20 μm wide) on PLGA were then fabricated through a mold method to further mimic myocardium anisotropy. The results demonstrated anisotropic mechanical and electrical properties and significantly improved cardiomyocyte density for up to 5 days on CNFs aligned in PLGA compared with being randomly oriented in PLGA. These results indicate that CNFs aligned in PLGA should be further explored for improving cardiomyocyte density, which is necessary in numerous cardiovascular applications.
doi:10.2147/IJN.S71587
PMCID: PMC4257053  PMID: 25489241
cardiomyocytes; poly(lactic-co-glycolic acid); carbon nanofibers; aligned; nanotechnology; anisotropy
6.  Physicochemical properties, cytotoxicity, and antimicrobial activity of sulphated zirconia nanoparticles 
Nanoparticle sulphated zirconia with Brønsted acidic sites were prepared here by an impregnation reaction followed by calcination at 600°C for 3 hours. The characterization was completed using X-ray diffraction, thermal gravimetric analysis, Fourier transform infrared spectroscopy, Brunner-Emmett-Teller surface area measurements, scanning electron microscopy with energy dispersive X-ray spectroscopy, and transmission electron microscopy. Moreover, the anticancer and antimicrobial effects were investigated for the first time. This study showed for the first time that the exposure of cancer cells to sulphated zirconia nanoparticles (3.9–1,000 μg/mL for 24 hours) resulted in a dose-dependent inhibition of cell growth, as determined by (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Similar promising results were observed for reducing bacteria functions. In this manner, this study demonstrated that sulphated zirconia nanoparticles with Brønsted acidic sites should be further studied for a wide range of anticancer and antibacterial applications.
doi:10.2147/IJN.S66058
PMCID: PMC4304593  PMID: 25632233
sulphated zirconia; nanoparticles; antimicrobial; anticancer
7.  Effect of the protein corona on nanoparticles for modulating cytotoxicity and immunotoxicity 
Although the cytotoxicity of nanoparticles (NPs) is greatly influenced by their interactions with blood proteins, toxic effects resulting from blood interactions are often ignored in the development and use of nanostructured biomaterials for in vivo applications. Protein coronas created during the initial reaction with NPs can determine the subsequent immunological cascade, and protein coronas formed on NPs can either stimulate or mitigate the immune response. Along these lines, the understanding of NP-protein corona formation in terms of physiochemical surface properties of the NPs and NP interactions with the immune system components in blood is an essential step for evaluating NP toxicity for in vivo therapeutics. This article reviews the most recent developments in NP-based protein coronas through the modification of NP surface properties and discusses the associated immune responses.
doi:10.2147/IJN.S72998
PMCID: PMC4275058  PMID: 25565807
nanostructured biomaterials; blood response; cytotoxicity; immunotoxicity; protein corona
8.  Lubricin as a novel nanostructured protein coating to reduce fibroblast density 
Excessive fibroblast adhesion and proliferation on the surface of medical implants (such as catheters, endotracheal tubes, intraocular lenses, etc) can lead to major postsurgical complications. This study showed that when coated on tissue culture polystyrene, lubricin, a nanostructured mucinous glycoprotein found in the synovial fluid of joints, decreased fibroblast density for up to 2 days of culture compared to controls treated with phosphate buffered saline (PBS). When examining why, similar antifibroblast density results were found when coating tissue culture polystyrene with bovine submaxillary mucin (BSM), an even smaller protein closely related to the central subregion of lubricin. Additionally, results from this study demonstrated that in contrast to BSM or controls (PBS-coated and non-coated samples), lubricin was better at preserving the health of nonadherent or loosely adherent fibroblasts; fibroblasts that did not adhere or loosely adhered on the lubricin-coated tissue culture polystyrene adhered and proliferated well for up to an additional day when they were reseeded on uncoated tissue culture polystyrene. In summary, this study provides evidence for the promise of nanostructured lubricin (and to a lesser extent BSM) to inhibit fibroblast adhesion and growth when coated on medical devices; lubricin should be further explored for numerous medical device applications.
doi:10.2147/IJN.S56439
PMCID: PMC4077603  PMID: 25028550
lubricin; antiadhesive; fibroblasts; mucin
9.  Development of a biocompatible nanodelivery system for tuberculosis drugs based on isoniazid-Mg/Al layered double hydroxide 
The primary challenge in finding a treatment for tuberculosis (TB) is patient non-compliance to treatment due to long treatment duration, high dosing frequency, and adverse effects of anti-TB drugs. This study reports on the development of a nanodelivery system that intercalates the anti-TB drug isoniazid into Mg/Al layered double hydroxides (LDHs). Isoniazid was found to be released in a sustained manner from the novel nanodelivery system in humans in simulated phosphate buffer solutions at pH 4.8 and pH 7.4. The nanodelivery formulation was highly biocompatible compared to free isoniazid against human normal lung and 3T3 mouse fibroblast cells. The formulation was active against Mycobacterium tuberculosis and gram-positive bacteria and gram-negative bacteria. Thus results show significant promise for the further study of these nanocomposites for the treatment of TB.
doi:10.2147/IJN.S63608
PMCID: PMC4200032  PMID: 25336952
tuberculosis; isoniazid; Mg/Al LDH; nanodelivery system
10.  Nanotechnology and picotechnology to increase tissue growth: a summary of in vivo studies 
The aim of tissue engineering is to develop functional substitutes for damaged tissues or malfunctioning organs. Since only nanomaterials can mimic the surface properties (ie, roughness) of natural tissues and have tunable properties (such as mechanical, magnetic, electrical, optical, and other properties), they are good candidates for increasing tissue growth, minimizing inflammation, and inhibiting infection. Recently, the use of nanomaterials in various tissue engineering applications has demonstrated improved tissue growth compared to what has been achieved until today with our conventional micron structured materials. This short report paper will summarize some of the more relevant advancements nanomaterials have made in regenerative medicine, specifically improving bone and bladder tissue growth. Moreover, this short report paper will also address the continued potential risks and toxicity concerns, which need to be accurately addressed by the use of nanomaterials. Lastly, this paper will emphasize a new field, picotechnology, in which researchers are altering electron distributions around atoms to promote surface energy to achieve similar increased tissue growth, decreased inflammation, and inhibited infection without potential nanomaterial toxicity concerns.
doi:10.2147/IJN.S58384
PMCID: PMC4024972  PMID: 24872699
nanomaterials; tissue engineering; toxicity
11.  Novel nano-rough polymers for cartilage tissue engineering 
This study presents an innovative method for creating a highly porous surface with nanoscale roughness on biologically relevant polymers, specifically polyurethane (PU) and polycaprolactone (PCL). Nanoembossed polyurethane (NPU) and nanoembossed polycaprolactone (NPCL) were produced by the casting of PU and PCL over a plasma-deposited, spiky nanofeatured crystalline titanium (Ti) surface. The variables used in the process of making the spiky Ti surface can be altered to change the physical properties of the spiky particles, and thus, the cast polymer substrate surface can be altered. The spiky Ti surface is reusable to produce additional nanopolymer castings. In this study, control plain PU and PCL polymers were produced by casting the polymers over a plain Ti surface (without spikes). All polymer surface morphologies were characterized using both scanning electron microscopy and atomic force microscopy, and their surface energies were measured using liquid contact angle measurements. The results revealed that both NPU and NPCL possessed a higher degree of nanometer surface roughness and higher surface energy compared with their respective unaltered polymers. Further, an in vitro study was carried out to determine chondrocyte (cartilage-producing cells) functions on NPU and NPCL compared with on control plain polymers. Results of this study provided evidence of increased chondrocyte numbers on NPU and NPCL compared with their respective plain polymers after periods of up to 7 days. Moreover, the results provide evidence of greater intracellular protein production and collagen secretion by chondrocytes cultured on NPU and NPCL compared with control plain polymers. In summary, the present in vitro results of increased chondrocyte functions on NPU and NPCL suggest these materials may be suitable for numerous polymer-based cartilage tissue-engineering applications and, thus, deserve further investigation.
doi:10.2147/IJN.S55865
PMCID: PMC3998868  PMID: 24790427
chondrocytes; polyurethane; polycaprolactone; nano-roughened polymers; cartilage applications
12.  Decreased Staphylococcus aureus and increased osteoblast density on nanostructured electrophoretic-deposited hydroxyapatite on titanium without the use of pharmaceuticals 
Background
Plasma-spray deposition of hydroxyapatite on titanium (Ti) has proven to be a suboptimal solution to improve orthopedic-implant success rates, as demonstrated by the increasing number of orthopedic revision surgeries due to infection, implant loosening, and a myriad of other reasons. This could be in part due to the high heat involved during plasma-spray deposition, which significantly increases hydroxyapatite crystal growth into the nonbiologically inspired micron regime. There has been a push to create nanotopographies on implant surfaces to mimic the physiological nanostructure of native bone and, thus, improve osteoblast (bone-forming cell) functions and inhibit bacteria functions. Among the several techniques that have been adopted to develop nanocoatings, electrophoretic deposition (EPD) is an attractive, versatile, and effective material-processing technique.
Objective
The in vitro study reported here aimed to determine for the first time bacteria responses to hydroxyapatite coated on Ti via EPD.
Results
There were six and three times more osteoblasts on the electrophoretic-deposited hydroxyapatite on Ti compared with Ti (control) and plasma-spray-deposited hydroxyapatite on Ti after 5 days of culture, respectively. Impressively, there were 2.9 and 31.7 times less Staphylococcus aureus on electrophoretic-deposited hydroxyapatite on Ti compared with Ti (control) and plasma-spray-deposited hydroxyapatite on Ti after 18 hours of culture, respectively.
Conclusion
Compared with uncoated Ti and plasma-sprayed hydroxyapatite coated on Ti, the results provided significant promise for the use of EPD to improve bone-cell density and be used as an antibacterial coating without resorting to the use of antibiotics.
doi:10.2147/IJN.S55733
PMCID: PMC3986289  PMID: 24748789
bacteria; nanotechnology; electrophoretic deposition; inhibition
13.  Synthesis, characterization, and antimicrobial activity of an ampicillin-conjugated magnetic nanoantibiotic for medical applications 
Because of their magnetic properties, magnetic nanoparticles (MNPs) have numerous diverse biomedical applications. In addition, because of their ability to penetrate bacteria and biofilms, nanoantimicrobial agents have become increasingly popular for the control of infectious diseases. Here, MNPs were prepared through an iron salt coprecipitation method in an alkaline medium, followed by a chitosan coating step (CS-coated MNPs); finally, the MNPs were loaded with ampicillin (amp) to form an amp-CS-MNP nanocomposite. Both the MNPs and amp-CS-MNPs were subsequently characterized and evaluated for their antibacterial activity. X-ray diffraction results showed that the MNPs and nanocomposites were composed of pure magnetite. Fourier transform infrared spectra and thermogravimetric data for the MNPs, CS-coated MNPs, and amp-CS-MNP nanocomposite were compared, which confirmed the CS coating on the MNPs and the amp-loaded nanocomposite. Magnetization curves showed that both the MNPs and the amp-CS-MNP nanocomposites were superparamagnetic, with saturation magnetizations at 80.1 and 26.6 emu g−1, respectively. Amp was loaded at 8.3%. Drug release was also studied, and the total release equilibrium for amp from the amp-CS-MNPs was 100% over 400 minutes. In addition, the antimicrobial activity of the amp-CS-MNP nanocomposite was determined using agar diffusion and growth inhibition assays against Gram-positive bacteria and Gram-negative bacteria, as well as Candida albicans. The minimum inhibitory concentration of the amp-CS-MNP nanocomposite was determined against bacteria including Mycobacterium tuberculosis. The synthesized nanocomposites exhibited antibacterial and antifungal properties, as well as antimycobacterial effects. Thus, this study introduces a novel β-lactam antibacterial-based nanocomposite that can decrease fungus activity on demand for numerous medical applications.
doi:10.2147/IJN.S61143
PMCID: PMC4134181  PMID: 25143729
iron oxide nanoparticles; chitosan; coating material; antibacterial activity; β-lactam; and nanoantibiotics
14.  Antimycobacterial, antimicrobial, and biocompatibility properties of para-aminosalicylic acid with zinc layered hydroxide and Zn/Al layered double hydroxide nanocomposites 
The treatment of tuberculosis by chemotherapy is complicated due to multiple drug prescriptions, long treatment duration, and adverse side effects. We report here for the first time an in vitro therapeutic effect of nanocomposites based on para-aminosalicylic acid with zinc layered hydroxide (PAS-ZLH) and zinc-aluminum layered double hydroxides (PAS-Zn/Al LDH), against mycobacteria, Gram-positive bacteria, and Gram-negative bacteria. The nanocomposites demonstrated good antimycobacterial activity and were found to be effective in killing Gram-positive and Gram-negative bacteria. A biocompatibility study revealed good biocompatibility of the PAS-ZLH nanocomposites against normal human MRC-5 lung cells. The para-aminosalicylic acid loading was quantified with high-performance liquid chromatography analysis. In summary, the present preliminary in vitro studies are highly encouraging for further in vivo studies of PAS-ZLH and PAS-Zn/Al LDH nanocomposites to treat tuberculosis.
doi:10.2147/DDDT.S63753
PMCID: PMC4122184  PMID: 25114509
Zn/Al-layered double hydroxides; zinc layered hydroxides; tuberculosis; para-aminosalicylic acid (PAS); antimicrobial agents
15.  Short communication: selective cytotoxicity of curcumin on osteosarcoma cells compared to healthy osteoblasts 
Curcumin is a natural phenolic compound extracted from the plant Curcuma longa L. In previous studies, curcumin has been shown to have anticancer, antioxidant, and anti-inflammatory effects. In this study, the cytotoxicity of different concentrations (5, 10, 25, 50, 75, and 100 μM) of curcumin dissolved in dimethyl sulfoxide was compared between MG-63 osteosarcoma and healthy human osteoblast cells. Consequently, the viability of osteosarcoma cells was less than 50% at a concentration of 10 μM compared to the control sample without curcumin, but healthy osteoblast cells had at least 80% viability throughout all the concentrations tested. The results demonstrated that MG-63 osteosarcoma cells were much more sensitive in terms of cytotoxicity to curcumin, while the healthy human osteoblasts exhibited a higher healthy viability after 24 hours of curcumin treatment. Therefore, this study showed that at the right concentrations (5 μM to 25 μM), curcumin, along with a proper nanoparticle drug delivery carrier, may selectively kill bone cancer cells over healthy bone cells.
doi:10.2147/IJN.S55505
PMCID: PMC3894136  PMID: 24453488
curcumin; osteosarcoma; human osteoblast; viability; bone cancer
16.  Understanding improved osteoblast behavior on select nanoporous anodic alumina 
The aim of this study was to prepare different sized porous anodic alumina (PAA) and examine preosteoblast (MC3T3-E1) attachment and proliferation on such nanoporous surfaces. In this study, PAA with tunable pore sizes (25 nm, 50 nm, and 75 nm) were fabricated by a two-step anodizing procedure in oxalic acid. The surface morphology and elemental composition of PAA were characterized by field emission scanning electron microscopy and X-ray photoelectron spectroscopy analysis. The nanopore arrays on all of the PAA samples were highly regular. X-ray photoelectron spectroscopy analysis suggested that the chemistry of PAA and flat aluminum surfaces were similar. However, contact angles were significantly greater on all of the PAA compared to flat aluminum substrates, which consequently altered protein adsorption profiles. The attachment and proliferation of preosteoblasts were determined for up to 7 days in culture using field emission scanning electron microscopy and a Cell Counting Kit-8. Results showed that nanoporous surfaces did not enhance initial preosteoblast attachment, whereas preosteoblast proliferation dramatically increased when the PAA pore size was either 50 nm or 75 nm compared to all other samples (P<0.05). Thus, this study showed that one can alter surface energy of aluminum by modifying surface nano-roughness alone (and not changing chemistry) through an anodization process to improve osteoblast density, and, thus, should be further studied as a bioactive interface for orthopedic applications.
doi:10.2147/IJN.S60346
PMCID: PMC4099197  PMID: 25045263
nanostructure; adhesion; proliferation; preosteoblast; orthopedics
17.  Greater fibroblast proliferation on an ultrasonicated ZnO/PVC nanocomposite material 
There has been a significant and growing concern over nosocomial medical device infections. Previous studies have demonstrated that embedding nanoparticles alone (specifically, zinc oxide [ZnO]) in conventional polymers (eg, polyvinyl chloride [PVC]) can decrease bacteria growth and may have the potential to prevent or disrupt bacterial processes that lead to infection. However, little to no studies have been conducted to determine mammalian cell functions on such a nanocomposite material. Clearly, for certain medical device applications, maintaining healthy mammalian cell functions while decreasing bacteria growth is imperative (yet uncommon). For this reason, in the presented study, ZnO nanoparticles of varying sizes (from 10 nm to >200 nm in diameter) and functionalization (including no functionalization to doping with aluminum oxide and functionalizing with a silane coupling agent KH550) were incorporated into PVC either with or without ultrasonication. Results of this study provided the first evidence of greater fibroblast density after 18 hours of culture on the smallest ZnO nanoparticle incorporated PVC samples with dispersion aided by ultrasonication. Specifically, the greatest amount of fibroblast proliferation was measured on ZnO nanoparticles functionalized with a silane coupling agent KH550; this sample exhibited the greatest dispersion of ZnO nanoparticles. Water droplet tests showed a general trend of decreased hydrophilicity when adding any of the ZnO nanoparticles to PVC, but an increase in hydrophilicity (albeit still below controls or pure PVC) when using ultrasonication to increase ZnO nanoparticle dispersion. Future studies will have to correlate this change in wettability to initial protein adsorption events that may explain fibroblast behavior. Mechanical tests also provided evidence of the ability to tailor mechanical properties of the ZnO/PVC nanocomposites through the use of the different ZnO nanoparticles. Coupled with previous antibacterial studies, the present study demonstrated that highly dispersed ZnO/PVC nanocomposite materials should be further studied for numerous medical device applications.
doi:10.2147/IJN.S54897
PMCID: PMC3883596  PMID: 24403831
ZnO; nanoparticles; PVC; fibroblast; dispersion; nanotechnology
18.  Development of a Highly Biocompatible Antituberculosis Nanodelivery Formulation Based on Para-Aminosalicylic Acid—Zinc Layered Hydroxide Nanocomposites 
The Scientific World Journal  2014;2014:401460.
Tuberculosis is a lethal epidemic, difficult to control disease, claiming thousands of lives every year. We have developed a nanodelivery formulation based on para-aminosalicylic acid (PAS) and zinc layered hydroxide using zinc nitrate salt as a precursor. The developed formulation has a fourfold higher efficacy of PAS against mycobacterium tuberculosis with a minimum inhibitory concentration (MIC) found to be at 1.40 μg/mL compared to the free drug PAS with a MIC of 5.0 μg/mL. The newly developed formulation was also found active against Gram-positive bacteria, Gram-negative bacteria, and Candida albicans. The formulation was also found to be biocompatible with human normal lung cells MRC-5 and mouse fibroblast cells-3T3. The in vitro release of PAS from the formulation was found to be sustained in a human body simulated phosphate buffer saline (PBS) solution at pH values of 7.4 and 4.8. Most importantly the nanocomposite prepared using zinc nitrate salt was advantageous in terms of yield and free from toxic zinc oxide contamination and had higher biocompatibility compared to one prepared using a zinc oxide precursor. In summary, these promising in vitro results are highly encouraging for the continued investigation of para-aminosalicylic acid and zinc layered hydroxide nanocomposites in vivo and eventual preclinical studies.
doi:10.1155/2014/401460
PMCID: PMC4094859  PMID: 25050392
19.  Antimicrobial and Controlled Release Studies of a Novel Nystatin Conjugated Iron Oxide Nanocomposite 
BioMed Research International  2014;2014:651831.
Nystatin is a tetraene diene polyene antibiotic showing a broad spectrum of antifungal activity. In the present study, we prepared a nystatin nanocomposite (Nyst-CS-MNP) by loading nystatin (Nyst) on chitosan (CS) coated magnetic nanoparticles (MNPs). The magnetic nanocomposites were characterized by X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), thermogravimetry analysis (TGA), vibrating sample magnetometer (VSM), and scanning electron microscopy (SEM). The XRD results showed that the MNPs and nanocomposite are pure magnetite. The FTIR analysis confirmed the binding of CS on the surface of the MNPs and also the loading of Nyst in the nanocomposite. The Nyst drug loading was estimated using UV-Vis instrumentation and showing a 14.9% loading in the nanocomposite. The TEM size image of the MNPs, CS-MNP, and Nyst-CS-MNP was 13, 11, and 8 nm, respectively. The release profile of the Nyst drug from the nanocomposite followed a pseudo-second-order kinetic model. The antimicrobial activity of the as-synthesized Nyst and Nyst-CS-MNP nanocomposite was evaluated using an agar diffusion method and showed enhanced antifungal activity against Candida albicans. In this manner, this study introduces a novel nanocomposite that can decrease fungus activity on-demand for numerous medical applications.
doi:10.1155/2014/651831
PMCID: PMC4037599  PMID: 24900976
20.  Using mathematical models to understand the effect of nanoscale roughness on protein adsorption for improving medical devices 
International Journal of Nanomedicine  2013;8(Suppl 1):75-81.
Surface roughness and energy significantly influence protein adsorption on to biomaterials, which, in turn, controls select cellular adhesion to determine the success and longevity of an implant. To understand these relationships at a fundamental level, a model was originally proposed by Khang et al to correlate nanoscale surface properties (specifically, nanoscale roughness and energy) to protein adsorption, which explained the greater cellular responses on nanostructured surfaces commonly reported in the literature today. To test this model for different surfaces from what was previously used to develop that model, in this study we synthesized highly ordered poly(lactic-co-glycolic acid) surfaces of identical chemistry but altered nanoscale surface roughness and energy using poly(dimethylsiloxane) molds of polystyrene beads. Fibronectin and collagen type IV adsorption studies showed a linear adsorption behavior as the surface nanoroughness increased. This supported the general trends observed by Khang et al. However, when fitting such data to the mathematical model established by Khang et al, a strong correlation did not result. Thus, this study demonstrated that the equation proposed by Khang et al to predict protein adsorption should be modified to accommodate for additional nanoscale surface property contributions (ie, surface charge) to make the model more accurate. In summary, results from this study provided an important step in developing future mathematical models that can correlate surface properties (such as nanoscale roughness and surface energy) to initial protein adsorption events important to promote select cellular adhesion. These criteria are critical for the fundamental understanding of the now well-documented increased tissue growth on nanoscale materials.
doi:10.2147/IJN.S47286
PMCID: PMC3790280  PMID: 24098081
nanophase topography; surface energy; collagen type IV; fibronectin; adsorption; modeling; nanoscale roughness; proteins
21.  Inhibited growth of Pseudomonas aeruginosa by dextran- and polyacrylic acid-coated ceria nanoparticles 
Ceria (CeO2) nanoparticles have been widely studied for numerous applications, but only a few recent studies have investigated their potential applications in medicine. Moreover, there have been almost no studies focusing on their possible antibacterial properties, despite the fact that such nanoparticles may reduce reactive oxygen species. In this study, we coated CeO2 nanoparticles with dextran or polyacrylic acid (PAA) because of their enhanced biocompatibility properties, minimized toxicity, and reduced clearance by the immune system. For the first time, the coated CeO2 nanoparticles were tested in bacterial assays involving Pseudomonas aeruginosa, one of the most significant bacteria responsible for infecting numerous medical devices. The results showed that CeO2 nanoparticles with either coating significantly inhibited the growth of Pseudomonas aeruginosa, by up to 55.14%, after 24 hours compared with controls (no particles). The inhibition of bacterial growth was concentration dependent. In summary, this study revealed, for the first time, that the characterized dextran- and PAA-coated CeO2 nanoparticles could be potential novel materials for numerous antibacterial applications.
doi:10.2147/IJN.S50292
PMCID: PMC3770513  PMID: 24039421
antibacterial; biomedical applications
22.  Nanostructured polyurethane-poly-lactic-co-glycolic acid scaffolds increase bladder tissue regeneration: an in vivo study 
Although showing much promise for numerous tissue engineering applications, polyurethane and poly-lactic-co-glycolic acid (PLGA) have suffered from a lack of cytocompatibility, sometimes leading to poor tissue integration. Nanotechnology (or the use of materials with surface features or constituent dimensions less than 100 nm in at least one direction) has started to transform currently implanted materials (such as polyurethane and PLGA) to promote tissue regeneration. This is because nanostructured surface features can be used to change medical device surface energy to alter initial protein adsorption events important for promoting tissue-forming cell functions. Thus, due to their altered surface energetics, the objective of the present in vivo study was to create nanoscale surface features on a new polyurethane and PLGA composite scaffold (by soaking the polyurethane side and PLGA side in HNO3 and NaOH, respectively) and determine bladder tissue regeneration using a minipig model. The novel nanostructured scaffolds were further functionalized with IKVAV and YIGSR peptides to improve cellular responses. Results provided the first evidence of increased in vivo bladder tissue regeneration when using a composite of nanostructured polyurethane and PLGA compared with control ileal segments. Due to additional surgery, extended potentially problematic healing times, metabolic complications, donor site morbidity, and sometimes limited availability, ileal segment repair of a bladder defect is not optimal and, thus, a synthetic analog is highly desirable. In summary, this study indicates significant promise for the use of nanostructured polyurethane and PLGA composites to increase bladder tissue repair for a wide range of regenerative medicine applications, such as regenerating bladder tissue after removal of cancerous tissue, disease, or other trauma.
doi:10.2147/IJN.S44901
PMCID: PMC3770520  PMID: 24039415
polyurethane; poly-lactic-co-glycolic acid; nanotechnology; nanostructured features; in vivo
23.  Colloidal graphite/graphene nanostructures using collagen showing enhanced thermal conductivity 
In the present study, the exfoliation of natural graphite (GR) directly to colloidal GR/graphene (G) nanostructures using collagen (CL) was studied as a safe and scalable process, akin to numerous natural processes and hence can be termed “biomimetic”. Although the exfoliation and functionalization takes place in just 1 day, it takes about 7 days for the nano GR/G flakes to stabilize. The predominantly aromatic residues of the triple helical CL forms its own special micro and nanoarchitecture in acetic acid dispersions. This, with the help of hydrophobic and electrostatic forces, interacts with GR and breaks it down to nanostructures, forming a stable colloidal dispersion. Surface enhanced Raman spectroscopy, X-ray diffraction, photoluminescence, fluorescence, and X-ray photoelectron spectroscopy of the colloid show the interaction between GR and CL on day 1 and 7. Differential interference contrast images in the liquid state clearly reveal how the GR flakes are entrapped in the CL fibrils, with a corresponding fluorescence image showing the intercalation of CL within GR. Atomic force microscopy of graphene-collagen coated on glass substrates shows an average flake size of 350 nm, and the hexagonal diffraction pattern and thickness contours of the G flakes from transmission electron microscopy confirm ≤ five layers of G. Thermal conductivity of the colloid shows an approximate 17% enhancement for a volume fraction of less than approximately 0.00005 of G. Thus, through the use of CL, this new material and process may improve the use of G in terms of biocompatibility for numerous medical applications that currently employ G, such as internally controlled drug-delivery assisted thermal ablation of carcinoma cells.
doi:10.2147/IJN.S57122
PMCID: PMC3956625  PMID: 24648728
graphene; collagen; colloid; nanostructures; biomimetic; carbon; nanomaterials; heat; thermal ablation; thermal conductivity
24.  Understanding the wetting properties of nanostructured selenium coatings: the role of nanostructured surface roughness and air-pocket formation 
Wetting properties of biomaterials, in particular nanomaterials, play an important role, as these influence interactions with biological elements, such as proteins, bacteria, and cells. In this study, the wetting phenomenon of titanium substrates coated with selenium nanoparticles was studied using experimental and mathematical modeling tools. Importantly, these selenium-coated titanium substrates were previously reported to increase select protein adsorption (such as vitronectin and fibronectin), to decrease bacteria growth, and increase bone cell growth. Increased selenium nanoparticle coating density resulted in higher contact angles but remained within the hydrophilic regime. This trend was found in disagreement with the Wenzel model, which is widely used to understand the wetting properties of rough surfaces. The trend also did not fit well with the Cassie–Baxter model, which was developed to understand the wetting properties of composite surfaces. A modified wetting model was thus proposed in this study, to understand the contributing factors of material properties to the hydrophilicity/hydrophobicity of these nanostructured selenium-coated surfaces. The analysis and model created in this study can be useful in designing and/or understanding the wetting behavior of numerous biomedical materials and in turn, biological events (such as protein adsorption as well as bacteria and mammalian cell functions).
doi:10.2147/IJN.S42970
PMCID: PMC3669097  PMID: 23737667
hydrophilicity, hydrophobicity, Wenzel model, Cassie; Baxter model, free energy, implant material, proteins, cells, bacteria
25.  Effects of chemically modified nanostructured PLGA on functioning of lung and breast cancer cells 
Background
The aim of this study was to investigate the effects of poly-lactic-co-glycolic acid (PLGA) nanotopographies with alginate or chitosan protein preadsorption on the functioning of healthy and cancerous lung and breast cells, including adhesion, proliferation, apoptosis, and release of vascular endothelial growth factor (VEGF), which promotes tumor angiogenesis and secretion.
Methods
We used a well established cast-mold technique to create nanoscale surface features on PLGA. Some of the nanomodified PLGA films were then exposed to alginate and chitosan. Surface roughness and the presence of protein was confirmed by atomic force microscopy. Surface energy was quantified by contact angle measurement.
Results
Nanostructured PLGA surfaces with 23 nm features decreased synthesis of VEGF in both lung and breast cancer cells compared with conventional PLGA. Preadsorbing alginate further decreased cancer cell function, with nanostructured PLGA preadsorbed with alginate achieving the greatest decrease in synthesis of VEGF in both lung and breast cancer cells. In contrast, compared with nonmodified smooth PLGA, healthy cell functions were either not altered (ie, breast) or were enhanced (ie, lung) by use of nanostructured features and alginate or chitosan protein preadsorption.
Conclusion
Using this technique, we developed surface nanometric roughness and modification of surface chemistry that could selectively decrease breast and lung cancer cell functioning without the need for chemotherapeutics. This technique requires further study in a wide range of anticancer and regenerative medicine applications.
doi:10.2147/IJN.S41570
PMCID: PMC3658439  PMID: 23696702
breast; lung; cancer; nanotechnology; alginate; chitosan

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