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Biomaterials (v.32, #24)

Editorial board (pp. ifc).

Role of the Toll-like receptor pathway in the recognition of orthopedic implant wear-debris particles by Jeremy I. Pearl; Ting Ma; Afraaz R. Irani; Zhinong Huang; William H. Robinson; Robert L. Smith; Stuart B. Goodman (pp. 5535-5542).
The inflammatory response to prosthetic implant-derived wear particles is the primary cause of bone loss and aseptic loosening of implants, but the mechanisms by which macrophages recognize and respond to particles remain unknown. Studies of innate immunity demonstrate that Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPS). All TLRs signal through myeloid differentiation factor 88 (MyD88), except TLR3 which signals through TIR domain containing adapter inducing interferon-beta (TRIF), and TLR4 which signals through both MyD88 and TRIF. We hypothesized that wear-debris particles may act as PAMPs/DAMPs and activate macrophages via TLRs. To test this hypothesis, we first demonstrated that inhibition of MyD88 decreases polymethylmethacrylate (PMMA) particle-induced production of TNF-α in RAW 264.7 macrophages. Next we compared particle-induced production of TNF-α among MyD88 knockout (MyD88−/−), TRIF knockout (TRIF−/−), and wild type (WT) murine macrophages. Relative to WT, disruption of MyD88 signaling diminished, and disruption of TRIF amplified the particle-induced production of TNF-α. Gene expression data indicated that this latter increase in TNF-α was due to a compensatory increase in expression of MyD88 associated components of the TLR pathway. Finally, using an in vivo model, MyD88−/− mice developed less particle-induced osteolysis than WT mice. These results indicate that the response to PMMA particles is partly dependent on MyD88, presumably as part of TLR signaling; MyD88 may represent a therapeutic target for prevention of wear debris-induced periprosthetic osteolysis.

Keywords: Osteolysis; Polymethylmethacrylate; Wear debris; Immune response

The fate of ultrafast degrading polymeric implants in the brain by Dan Y. Lewitus; Karen L. Smith; William Shain; Durgadas Bolikal; Joachim Kohn (pp. 5543-5550).
We have recently reported on an ultrafast degrading tyrosine-derived terpolymer that degrades and resorbs within hours, and is suitable for use in cortical neural prosthetic applications. Here we further characterize this polymer, and describe a new tyrosine-derived fast degrading terpolymer in which the poly(ethylene glycol) (PEG) is replaced by poly(trimethylene carbonate) (PTMC). This PTMC containing terpolymer showed similar degradation characteristics but its resorption was negligible in the same period. Thus, changes in the polymer chemistry allowed for the development of two ultrafast degrading polymers with distinct difference in resorption properties. The in vivo tissue response to both polymers used as intraparenchymal cortical devices was compared to poly(lactic-co-glycolic acid) (PLGA). Slow resorbing, indwelling implant resulted in continuous glial activation and loss of neural tissue. In contrast, the fast degrading tyrosine-derived terpolymer that is also fast resorbing, significantly reduced both the glial response in the implantation site and the neuronal exclusion zone. Such polymers allow for brain tissue recovery, thus render them suitable for neural interfacing applications.

Keywords: Brain tissue response; Biodegradation; Bioerosion; Ultrafast degrading polymers; Tyrosine-derived terpolymer

Highly stable carbon nanotube doped poly(3,4-ethylenedioxythiophene) for chronic neural stimulation by Xiliang Luo; Cassandra L. Weaver; David D. Zhou; Robert Greenberg; Xinyan T. Cui (pp. 5551-5557).
The function and longevity of implantable microelectrodes for chronic neural stimulation depends heavily on the electrode materials, which need to present high charge injection capability and high stability. While conducting polymers have been coated on neural microelectrodes and shown promising properties for chronic stimulation, their practical applications have been limited due to unsatisfying stability. Here, poly(3,4-ethylenedioxythiophene) (PEDOT) doped with pure carbon nanotubes (CNTs) was electrochemically deposited on Pt microelectrodes to evaluate its properties for chronic stimulation. The PEDOT/CNT coated microelectrodes demonstrated much lower impedance than the bare Pt, and the PEDOT/CNT film exhibited excellent stability. For both acute and chronic stimulation tests, there is no significant increase in the impedance of the PEDOT/CNT coated microelectrodes, and none of the PEDOT/CNT films show any cracks or delamination, which have been the limitation for many conducting polymer coatings on neural electrodes. The charge injection limit of the Pt microelectrode was significantly increased to 2.5 mC/cm2 with the PEDOT/CNT coating. Further in vitro experiments also showed that the PEDOT/CNT coatings are non-toxic and support the growth of neurons. It is expected that this highly stable PEDOT/CNT composite may serve as excellent new material for neural electrodes.

Keywords: Chronic neural stimulation; Poly(3,4-ethylenedioxythiophene); Carbon nanotubes; Neural electrodes; PEDOT

Enhancement of cell retention and functional benefits in myocardial infarction using human amniotic-fluid stem-cell bodies enriched with endogenous ECM by Wen-Yu Lee; Hao-Ji Wei; Wei-Wen Lin; Yi-Chun Yeh; Shiaw-Min Hwang; Jiun-Jie Wang; Ming-Song Tsai; Yen Chang; Hsing-Wen Sung (pp. 5558-5567).
Stem cell transplantation may repair the infarcted heart. Despite the encouraging preliminary results, an optimal cell type used and low retention of the transplanted cells remain to be overcome. In this study, a multiwelled methylcellulose hydrogel system was used to cultivate human amniotic-fluid stem cells (hAFSCs) to form spherically symmetric cell bodies for cellular cardiomyoplasty. The grown hAFSC bodies enriched with extracellular matrices (ECM) were xenogenically transplanted in the peri-infarct area of an immune-suppressed rat, via direct intramyocardial injection. Results of bioluminescence imaging and real-time PCR revealed that hAFSC bodies could considerably enhance cell retention and engraftment in short-term and long-term observations, when compared with dissociated hAFSCs. Echocardiography and magnetic resonance imaging showed that the enhanced cell engraftment in the hAFSC-body group could significantly attenuate the progression of heart failure, improve the global function, and increase the regional wall motion. At the infarct, expressions of HGF, bFGF and VEGF were significantly up-regulated, an indication of the significantly increased vessel densities in the hearts treated with hAFSC bodies. The injected hAFSC bodies could undergo differentiation into angiogenic and cardiomyogenic lineages and contribute to functional benefits by direct regeneration. The aforementioned results demonstrate that hAFSC bodies can attenuate cell loss after intramuscular injection by providing an adequate physical size and offering an enriched ECM environment to retain the transplanted cells in the myocardium, thus improving heart function.

Keywords: Methylcellulose hydrogel; Cell body; Cell therapy; Tissue regeneration; Myocardial infarction

The stimulation of the cardiac differentiation of mesenchymal stem cells in tissue constructs that mimic myocardium structure and biomechanics by Jianjun Guan; Feng Wang; Zhenqing Li; Joseph Chen; Xiaolei Guo; Jun Liao; Nicanor I. Moldovan (pp. 5568-5580).
We investigated whether tissue constructs resembling structural and mechanical properties of the myocardium would induce mesenchymal stem cells (MSCs) to differentiate into a cardiac lineage, and whether further mimicking the 3-D cell alignment of myocardium would enhance cardiac differentiation. The tissue constructs were generated by integrating MSCs with elastic polyurethane nanofibers in an electrical field. Control of processing parameters resulted in tissue constructs recapitulating the fibrous and anisotropic structure, and typical stress-strain response of native porcine myocardium. MSCs proliferated in the tissue constructs when cultured dynamically, but retained a round morphology. mRNA expression demonstrated that cardiac differentiation was significantly stimulated. Enhanced cardiac differentiation was achieved by 3-D alignment of MSCs within the tissue constructs. Cell alignment was attained by statically stretching tissue constructs during culture. Increasing stretching strain from 25% to 75% increased the degree of 3-D cell alignment. Real time RT-PCR results showed that when cells assuming a high degree of alignment (with application of 75% strain), their expression of cardiac markers (GATA4, Nkx2.5 and MEF2C) remarkably increased. The differentiated cells also developed calcium channels, which are required to have electrophysiological properties. This report to some extent explains the outcome of many in vivo studies, where only a limited amount of the injected MSCs differentiated into cardiomyocytes. It is possible that the strain of the heartbeat (∼20%) cannot allow the MSCs to have an alignment high enough for a remarkable cardiac differentiation. This work suggests that pre-differentiation of MSCs into cardiomyocytes prior to injection may result in a greater degree of cardiac regeneration than simply injecting un-differentiated MSCs into heart.

Keywords: Electrospinning; Tissue-specific constructs; Mesenchymal stem cell; Myocardium

A 3D cartilage – Inflammatory cell culture system for the modeling of human osteoarthritis by Lin Sun; Xiuli Wang; David L. Kaplan (pp. 5581-5589).
Inflammation plays a major role in the destruction of cartilage in osteoarthritis (OA), with the interaction of multiple mediators, immune cells, fibroblasts and chondrocytes. Current 2D studies in vitro with cell lines, as well as animal models, are limited in terms of providing insight into pathogenic mechanisms related to the human system. Hence, an in vitro human 3D cartilage tissue system was established to study the impact of inflammatory mediators on chondrocytes and matrices as an initial approach to emulating early stages of OA. An in vitro 3D human cartilage tissue system was established by culturing primary chondrocytes in silk protein porous scaffolds up to 21 days in static culture, with and without cytokine (IL-1β and TNF-α) exposure or with the use of macrophage conditioned medium (MCM). To assess chondrocyte responses, transcript levels, histology and immunohistochemistry were used to assess changes in cell viability and in cartilage matrix composition, including collagen type II and aggrecan. Chondrocyte hypertrophy and apoptosis were assessed via collagen type X and caspase-3. RT-PCR revealed that the cytokines and the MCM regulated matrix-related gene expression of chondrocytes, but with different outcomes. For anabolic-encoding genes, MCM suppressed collagen type II and upregulated aggrecan. In contrast, the cytokines suppressed aggrecan formation and had no effect on collagen type II. For catabolic-encoded genes, both cytokines and MCM upregulated MMP1, MMP3, MMP13 and ADAMTS4, with cytokines preferentially upregulating MMP13 and MCM upregulating ADMTS4. MCM down-regulated ADAMTS5. In addition, MCM stimulation led to hypertrophy and apoptosis of chondrocytes, outcomes not found with the cytokine treatment group. A decrease in aggrecan content with cytokines and MCM stimulation was found, while MCM resulted in greater reduction than the cytokine treatment. The results demonstrated that OA-like features, such as changes in matrix synthesis gene expression, increase of collagense gene expression and loss of aggrecan, were initiated within this 3D chrondrocyte human tissue system upon stimulation of the cultures with cytokines and MCM. MCM was a better inducer of immune-related features of OA, because besides the features found with cytokine stimulation, the MCM treatment also initiated collagen X expression and deposition and apoptosis of chondrocytes, important features of human OA. The results obtained with this new in vitro tissue model provide an initial step towards the development of an early stage OA system to allow for more systematic study and insight into the origins and outcomes with this disease.

Keywords: Osteoarthritis; Tissue engineered cartilage; Inflammation; Silk

Surface functionalization of hyaluronic acid hydrogels by polyelectrolyte multilayer films by Seda Yamanlar; Shilpa Sant; Thomas Boudou; Catherine Picart; Ali Khademhosseini (pp. 5590-5599).
Hyaluronic acid (HA), an anionic polysaccharide, is one of the major components of the natural extracellular matrix (ECM). Although HA has been widely used for tissue engineering applications, it does not support cell attachment and spreading and needs chemical modification to support cellular adhesion. Here, we present a simple approach to functionalize photocrosslinked HA hydrogels by deposition of poly(l-lysine) (PLL) and HA multilayer films made by the layer-by-layer (LbL) technique. PLL/HA multilayer film formation was assessed by using fluorescence microscopy, contact angle measurements, cationic dye loading and confocal microscopy. The effect of polyelectrolyte multilayer film (PEM) formation on the physicochemical and mechanical properties of hydrogels revealed polyelectrolyte diffusion inside the hydrogel pores, increased hydrophobicity of the surface, reduced equilibrium swelling, and reduced compressive moduli of the modified hydrogels. Furthermore, NIH-3T3 fibroblasts seeded on the surface showed improved cell attachment and spreading on the multilayer functionalized hydrogels. Thus, modification of HA hydrogel surfaces with multilayer films affected their physicochemical properties and improved cell adhesion and spreading on these surfaces. This new hydrogel/PEM composite system may offer possibilities for various biomedical and tissue engineering applications, including growth factor delivery and co-culture systems.

Keywords: Hyaluronic acid hydrogels; Photocrosslinked; Surface functionalization; Layer-by-layer; Polyelectrolyte diffusion; Cell adhesion

Effects of biomimetic surfaces and oxygen tension on redifferentiation of passaged human fibrochondrocytes in 2D and 3D cultures by Guak-Kim Tan; Donna Lee M. Dinnes; Peter T. Myers; Justin J. Cooper-White (pp. 5600-5614).
Due to its limited healing potential within the inner avascular region, functional repair of the meniscus remains a significant challenge in orthopaedic surgery. Tissue engineering of a meniscus implant using meniscal cells offers the promise of enhancing the reparative process and achieving functional meniscal repair. In this work, using quantitative real-time reverse transcriptase polymerase chain reaction (RT-qPCR) analysis, we show that human fibrochondrocytes rapidly dedifferentiate during monolayer expansion on standard tissue culture flasks, representing a significant limit to clinical use of this cell population for meniscal repair. Previously, we have characterized and described the feasibility of a tailored biomimetic surface (C6S surface) for reversing dedifferentiation of monolayer-expanded rat meniscal cells. The surface is comprised of major meniscal extracellular matrix (ECM) components in the inner region, namely collagen I/II (at a 2:3 ratio) and chondroitin-6-sulfate. We thus have further evaluated the effects of the C6S surface, alongside a number of other tailored surfaces, on cell adhesion, proliferation, matrix synthesis and relevant marker gene expression (collagen I, –II, aggrecan and Sox-9 etc) of passaged human fibrochondrocytes in 2D (coated glass coverslips) and 3D (surface-modified polymeric scaffolds) environments. We show that the C6S surface is permissive for cell adhesion, proliferation and ECM synthesis, as demonstrated using DNA quantification, 1,9-dimethylmethylene blue (DMMB) assay, histology and immunohistochemistry. More importantly, RT-qPCR analyses corroborate the feasibility of the C6S surface for reversing phenotypic changes, especially the downregulation of collagen II, of dedifferentiated human fibrochondrocytes. Furthermore, human fibrochondrocyte redifferentiation was enhanced by hypoxia in the 3D cultures, independent of hypoxia inducible factor (HIF) transcriptional activity and was shown to potentially involve the transcriptional activation of Sox-9.

Keywords: Meniscal tissue engineering; Biomimetic; Redifferentiation; Hypoxia; Chondroitin sulfate; Collagen

Electrospun nanofibers as a tool for architecture control in engineered cardiac tissue by Yuliya Orlova; Nobuyuki Magome; Li Liu; Yong Chen; Konstantin Agladze (pp. 5615-5624).
This paper presents an in vitro system for cardiac tissue engineering based on cardiomyocytes cultured on electrospun polymethylglutarimide (PMGI) nanofibrous meshes either imprinted on solid substrate or suspended in space. Special care was taken over the ability to control the tissue architecture. The electrospinning process allowed nano-scale diameter PMGI fibers with different positioning density to be collected in a random or in an aligned way that defines the general configuration of the mesh. Micro-imprinted on solid substrate nanofibers guarantee aligned cell growth, when the distance between them is 30 μm or less. Suspended in 3D space, nanofibers define the overall architecture of the tissue, depending on orientation and positioning density of the nanofibers. As a result, cardiac cells proliferated into contractile tissue filaments, open-worked tissue meshes and continuous anisotropic cell sheets. Alignment of the cells was characterized by elongation of the cell shape and orientation of the α-actin filaments supported by the FFT data. The advantage of this method is its ability to maintain both three-dimensionality and structural anisotropy.

Keywords: Cardiac tissue engineering; Polymethylglutarimide; Electrospinning; Nanofibers; Cell culture

Stacking of aligned cell sheets for layer-by-layer control of complex tissue structure by Corin Williams; Angela W. Xie; Masayuki Yamato; Teruo Okano; Joyce Y Wong (pp. 5625-5632).
Children suffering from congenital heart defects (CHD) often require vascular reconstruction. Pediatric patients would greatly benefit from a cell-based tissue engineered vascular patch (TEVP) that has potential for growth. As artery structure and function are intimately linked, mimicking native tissue organization is an important design consideration. In this study, we cultured human mesenchymal stem cell on patterned thermo-responsive substrates. Cell alignment improved over time up to 2 wk in culture when sheets were ready for harvest. We then used cell sheets as “functional units” to build complex tissue structures that mimic native vascular smooth muscle cell organization in the medial layer of the artery. Cell sheets could be stacked using a gelatin stamp such that individual sheets in the construct were well aligned with each other (mimic of circumferential orientation) or at angles with respect to each other (mimic of herringbone structure). Controlling tissue organization layer-by-layer will be a powerful approach to building tissues with well defined and complex structure.

Keywords: Tissue engineering; Microcontact printing; Poly(; N; -isopropylacrylamide); Mesenchymal stem cell

Microscale mechanisms of agarose-induced disruption of collagen remodeling by Theresa A. Ulrich; Tae Geol Lee; Hyun Kyong Shon; Dae Won Moon; Sanjay Kumar (pp. 5633-5642).
Cells are strongly influenced by the local structure and mechanics of the extracellular matrix (ECM). We recently showed that adding agarose to soft collagen ECMs can mechanically stiffen these hydrogels by two orders of magnitude while limiting 3D cell motility, which we speculated might derive from agarose-mediated inhibition of collagen fiber deformation and remodeling. Here, we directly address this hypothesis by investigating the effects of agarose on cell–collagen interactions at the microscale. Addition of agarose progressively restricts cell spreading, reduces stress fiber and focal adhesion assembly, and inhibits macroscopic gel compaction. While time-of-flight secondary ion mass spectrometry and scanning electron microscopy fail to reveal agarose-induced alterations in collagen ligand presentation, the latter modality shows that agarose strongly impairs cell-directed assembly of large collagen bundles. Agarose-mediated inhibition of cell spreading and cytoarchitecture can be rescued by β-agarase digestion or by covalently crosslinking the matrix with glutaraldehyde. Based on these results, we argue that cell spreading and motility on collagen requires local matrix stiffening, which can be achieved via cell-mediated fiber remodeling or by chemically crosslinking the fibers. These findings provide new mechanistic insights into the regulatory function of agarose and bear general implications for cell adhesion and motility in fibrous ECMs.

Keywords: Brain; Cell adhesion; Hydrogel; ECM (extracellular matrix); Mechanical properties; Elasticity

Sustained targeting of Bcr–Abl + leukemia cells by synergistic action of dual drug loaded nanoparticles and its implication for leukemia therapy by Sarbari Acharya; Sanjeeb K. Sahoo (pp. 5643-5662).
Chimeric Bcr–Abl oncoprotein is the molecular hallmark of chronic myeloid leukemia (CML) and hence a lucrative target for therapeutic intervention of CML.However, limited efficacy of current first line treatment for CML calls attention for further development of more efficient strategies. Recently, much attention has been given to nanoparticle (NP) based drug delivery systems loaded with dual drugs to improve current disease therapies by overcoming toxicity and other side effects associated with high doses of single drugs. In the present study, we document to explore an approach to simultaneously deliver two drugs at target sites (i.e. Bcr–Abl oncoprotein) using poly (lactide-co-glycolide) (PLGA) nanoparticles. Preliminary study included screening six different anticancer drugs and their nanoformulations on leukemia cells. Results confirmed superlative antileukemic activity of paclitaxel (especially in formulations) on model cell line K562, but only upon longer exposure. Thus to lower time of action of such a potent drug, different drug combination were experimented taking the advantage of synergistic action of both the drugs. Evaluation at molecular and genetic level helped to identify signaling pathways upstream and downstream of Bcr–Abl, leading to its suppression. Results helped to illustrate dynamic changes primarily involved in inducing apoptotic activities on drug exposure of leukemia cells, thereby facilitating us to integrate different drug combinations in a more specific manner in near future to study CML in clinical settings.

Keywords: Chronic myeloid leukemia; Dual drug; Synergistic action; Sustain release; Apoptosis; Signaling pathway

Vitamin E (d-alpha-tocopheryl-co-poly(ethylene glycol) 1000 succinate) micelles-superparamagnetic iron oxide nanoparticles for enhanced thermotherapy and MRI by Prashant Chandrasekharan; Dipak Maity; Cai Xian Yong; Kai-Hsiang Chuang; Jun Ding; Si-Shen Feng (pp. 5663-5672).
We synthesized vitamin E TPGS (d-α-Tocopheryl-co-poly(ethylene glycol) 1000 succinate) micelles for superparamagnetic iron oxides formulation for nanothermotherapy and magnetic resonance imaging (MRI), which showed better thermal and magnetic properties, and in vitro cellular uptake and lower cytotoxicity as well as better in vivo therapeutic and imaging effects in comparison with the commercial Resovist® and the Pluronic®F127 micelles reported in the recent literature. The superparamagnetic iron oxides originally coated with oleic acid and oleylamine were formulated in the core of the TPGS micelles using a simple solvent-exchange method. The IOs-loaded TPGS showed greatest colloidal stability due to the critical micelle concentration (CMC) of vitamin E TPGS. Highly monodisperse and water soluble suspension was obtained which were stable in 0.9% normal saline for a period of 12 days. The micelles were characterized for their size and size distribution. Their morphology was examined through transmission electron microscopy (TEM). The enhanced thermal and superparamagnetic properties of the IOs-loaded TPGS micelles were assessed. Cellular uptake and cytotoxicity were investigated in vitro with MCF-7 cancer cells. Relaxivity study showed that the IOs-loaded TPGS micelles can have better effects for T2-weighted imaging using MRI. T2 mapped images of xenograft grown on SCID mice showed that the TPGS micelle formulation of IOs had ∼1.7 times and ∼1.05 times T2 decrease at the tumor site compared to Resovist® and the F127 micelle formulation, respectively.

Keywords: Cancer nanotechnology; Colloidal stability; Magnetic micelles; Molecular imaging; Nanothermotherapy; Xenograft tumor model

The use of mitochondrial targeting resveratrol liposomes modified with a dequalinium polyethylene glycol-distearoylphosphatidyl ethanolamine conjugate to induce apoptosis in resistant lung cancer cells by Xiao-Xing Wang; Yang-Bing Li; Hong-Juan Yao; Rui-Jun Ju; Yan Zhang; Ruo-Jing Li; Yang Yu; Liang Zhang; Wan-Liang Lu (pp. 5673-5687).
Intrinsic multidrug resistance (MDR) of cancers remains a major obstacle to successful chemotherapy. A dequalinium polyethylene glycol-distearoylphosphatidylethanolamine (DQA-PEG2000-DSPE) conjugate was synthesized as a mitochondriotropic molecule, and mitochondrial targeting resveratrol liposomes were developed by modifying DQA-PEG2000-DSPE on the surface of liposomes for overcoming the resistance. Evaluations were performed on the human lung adenocarcinoma A549 cells and resistant A549/cDDP cells, A549 and A549/cDDP tumor spheroids as well as the xenografted resistant A549/cDDP cancers in nude mice. The yield of DQA-PEG2000-DSPE conjugate synthesized was about 87% and the particle size of mitochondrial targeting resveratrol liposomes was approximately 70 nm. The mitochondrial targeting liposomes significantly enhanced the cellular uptake, and selectively accumulated into mitochondria when encapsulating coumarin as the fluorescent probe. Furthermore, mitochondrial targeting resveratrol liposomes induced apoptosis of both non-resistant and resistant cancer cells by dissipating mitochondria membrane potential, releasing cytochrome c and increasing the activities of caspase 9 and 3. They also exhibited significant antitumor efficacy in two kinds of cancer cells, in tumor spheroids by penetrating deeply into the core, and in xenografted resistant A549/cDDP cancers in nude mice. Mitochondrial targeting resveratrol liposomes co-treating with vinorelbine liposomes significantly enhanced the anticancer efficacy against the resistant A549/cDDP cells. In conclusion, mitochondrial targeting resveratrol liposomes would provide a potential strategy to treat the intrinsic resistant lung cancers by inducing apoptosis via mitochondria signaling pathway.

Keywords: DQA-PEG; 2000; -DSPE conjugate; Mitochondrial targeting resveratrol liposomes; Mitochondria signaling pathway; Intrinsic multidrug resistance; Lung cancer

Controlled epi-cortical delivery of epidermal growth factor for the stimulation of endogenous neural stem cell proliferation in stroke-injured brain by Michael J. Cooke; Yuanfei Wang; Cindi M. Morshead; Molly S. Shoichet (pp. 5688-5697).
One of the challenges in treating central nervous system (CNS) disorders with biomolecules is achieving local delivery while minimizing invasiveness. For the treatment of stroke, stimulation of endogenous neural stem/progenitor cells (NSPCs) by growth factors is a promising strategy for tissue regeneration. Epidermal growth factor (EGF) enhances proliferation of endogenous NSPCs in the subventricular zone (SVZ) when delivered directly to the ventricles of the brain; however, this strategy is highly invasive. We designed a biomaterials-based strategy to deliver molecules directly to the brain without tissue damage. EGF or poly(ethylene glycol)-modified EGF (PEG-EGF) was dispersed in a hyaluronan and methylcellulose (HAMC) hydrogel and placed epi-cortically on both uninjured and stroke-injured mouse brains. PEG-modification decreased the rate of EGF degradation by proteases, leading to a significant increase in protein accumulation at greater tissue depths than previously shown. Consequently, EGF and PEG-EGF increased NSPC proliferation in uninjured and stroke-injured brains; and in stroke-injured brains, PEG-EGF significantly increased NSPC stimulation. Our epi-cortical delivery system is a minimally-invasive method for local delivery to the brain, providing a new paradigm for local delivery to the brain.

Keywords: Hydrogel; Stroke; Epidermal growth factor; Tissue penetration; Poly(ethylene glycol); Drug delivery

Extended release of high molecular weight hydroxypropyl methylcellulose from molecularly imprinted, extended wear silicone hydrogel contact lenses by Charles J. White; Matthew K. McBride; Kayla M. Pate; Arianna Tieppo; Mark E. Byrne (pp. 5698-5705).
Symptoms of contact lenses induced dry eye (CLIDE) are typically treated through application of macromolecular re-wetting agents via eye drops. Therapeutic soft contact lenses can be formulated to alleviate CLIDE symptoms by slowly releasing comfort agent from the lens. In this paper, we present an extended wear silicone hydrogel contact lens with extended, controllable release of 120 kDa hydroxypropyl methylcellulose (HPMC) using a molecular imprinting strategy. A commercial silicone hydrogel lens was tailored to release approximately 1000 μg of HPMC over a period of up to 60 days in a constant manner at a rate of 16 μg/day under physiological flowrates, releasing over the entire range of continuous wear. Release rates could be significantly varied by the imprinting effect and functional monomer to template ratio (M/T) with M/T values 0, 0.2, 2.8, 3.4 corresponding to HPMC release durations of 10, 13, 23, and 53 days, respectively. Lenses had high optical quality and adequate mechanical properties for contact lens use. This work highlights the potential of imprinting in the design and engineering of silicone hydrogel lenses to release macromolecules for the duration of wear, which may lead to decreased CLIDE symptoms and more comfortable contact lenses.

Keywords: Silicone hydrogel contact lenses; Biomimetic molecular imprinting; Drug-eluting contact lenses; Contact lens induced dry eye (CLIDE); Re-wetting/comfort agent; Extended wear contact lenses

Antibacterial nano-structured titania coating incorporated with silver nanoparticles by Lingzhou Zhao; Hairong Wang; Kaifu Huo; Lingyun Cui; Wenrui Zhang; Hongwei Ni; Yumei Zhang; Zhifen Wu; Paul K. Chu (pp. 5706-5716).
Titanium (Ti) implants are widely used clinically but post-operation infection remains one of the most common and serious complications. A surface boasting long-term antibacterial ability is highly desirable in order to prevent implant associated infection. In this study, titania nanotubes (TiO2-NTs) incorporated with silver (Ag) nanoparticles are fabricated on Ti implants to achieve this purpose. The Ag nanoparticles adhere tightly to the wall of the TiO2-NTs prepared by immersion in a silver nitrate solution followed by ultraviolet light radiation. The amount of Ag introduced to the NTs can be varied by changing processing parameters such as the AgNO3 concentration and immersion time. The TiO2-NTs loaded with Ag nanoparticles (NT-Ag) can kill all the planktonic bacteria in the suspension during the first several days, and the ability of the NT-Ag to prevent bacterial adhesion is maintained without obvious decline for 30 days, which are normally long enough to prevent post-operation infection in the early and intermediate stages and perhaps even late infection around the implant. Although the NT-Ag structure shows some cytotoxicity, it can be reduced by controlling the Ag release rate. The NT-Ag materials are also expected to possess satisfactory osteoconductivity in addition to the good biological performance expected of TiO2-NTs. This controllable NT-Ag structure which provides relatively long-term antibacterial ability and good tissue integration has promising applications in orthopedics, dentistry, and other biomedical devices.

Keywords: Titania nanotubes; Ag nanoparticles; Antibacterial properties; Osteoblasts; Cytotoxicity

Cell transcytosing poly-arginine coated magnetic nanovector for safe and effective siRNA delivery by Omid Veiseh; Forrest M. Kievit; Hyejung Mok; Joseph Ayesh; Cassra Clark; Chen Fang; Matthew Leung; Hamed Arami; James O. Park; Miqin Zhang (pp. 5717-5725).
Lack of safe and effective carriers for delivery of RNA therapeutics remains a barrier to its broad clinical application. We report the development of a cell tanscytosing magnetic nanovector engineered as an siRNA carrier. Iron oxide nanoparticles were modified with poly(ethylene glycol) (PEG), small interfering RNA (siRNA), and a cationic polymer layer. Three nanovector formulations with cationic polymer coatings of poly-arginine (pArg), polylysine (pLys), and polyethylenimine (PEI), respectively, were prepared. The three nanovector formulations where evaluated for safety and ability to promote gene silencing in three types of cancer cells C6/GFP+, MCF7/GFP+, and TC2/GFP+, mimicking human cancers of the brain, breast, and prostate, respectively. Cell viability and fluorescence quantification assays revealed that pArg-coated nanovectors were most effective in promoting gene knockdown and least toxic of the three nanovector formulations tested. Transmission electron microscopy (TEM) imaging of nanovector treated cells further demonstrated that pArg-coated nanovectors enter cells through cell transcytosis, while pLys and PEI coated nanovectors enter cells endocytosis. Our findings suggest that NPs engineered to exploit the cell transcytosis intracellular trafficking pathway may offer a more safe and efficient route for siRNA delivery.

Keywords: Iron oxide nanoparticle; Gene therapy; Transcytosis; Cancer; MRI; siRNA

Enhancement of ectopic osteoid formation following the dual release of bone morphogenetic protein 2 and Wnt1 inducible signaling pathway protein 1 from gelatin sponges by Hiroshi Kohara; Yasuhiko Tabata (pp. 5726-5732).
Bone morphogenetic protein (BMP) 2-incorporated gelatin sponge is effective for in vivo osteoinduction. However, the modeling capacity of bone decreases with age. As atrial to stimulate effective bone formation for animals with decreased osteogenic potential, Wnt1 inducible signaling pathway protein (WISP) 1, an osteoblastic regulator, was combined with gelatin sponge incorporating BMP2. Osteopontin ( Opn) geneexpression was increased in vitro for mouse bone marrow stromal cells (BMSC) cultured in gelatin sponges incorporating BMP2 and WISP1 compared with those incorporating BMP2 or WISP1 alone. In vivo synergistic effect of BMP2 and WISP1 on the ectopic osteoid formation was observed when gelatin sponges incorporating BMP2 and WISP1 were implanted subcutaneously into middle-aged mice with decreased bone formation potential. It is concluded that the scaffold incorporating multiple osteoinductive agents could be effective in inducing bone formation in those with age-related decreased potential of bone formation.

Keywords: Controlled release; BMP2; WISP1; Bone formation; Age-related change

Endosomal escape and the knockdown efficiency of liposomal-siRNA by the fusogenic peptide shGALA by Yu Sakurai; Hiroto Hatakeyama; Yusuke Sato; Hidetaka Akita; Kentaro Takayama; Sachiko Kobayashi; Shiroh Futaki; Hideyoshi Harashima (pp. 5733-5742).
An siRNA that specifically silences the expression of mRNA is a potential therapeutic agent for dealing with many diseases including cancer. However, the poor cellular uptake and bioavailability of siRNA remains a major obstacle to clinical development. For efficient delivery to tumor tissue, the pharmacokinetics and intracellular trafficking of siRNA must be rigorously controlled. To address this issue, we developed a liposomal siRNA carrier, a multi-functional nano device (MEND). We describe herein an approach for systemic siRNA delivery to tumors by combining the MEND system with shGALA, a fusogenic peptide. In cultured cell experiments, shGALA-modification enhanced the endosomal escape of siRNA encapsulated in a polyethylene glycol modified MEND (PEG-MEND), resulting in an 82% knockdown of the target gene. In vivo systemic administration clarified that the shGALA-modified MEND (shGALA-MEND) showed 58% gene silencing in tumor tissues at a dose of 4 mg of siRNA/kg body weight. In addition, a significant inhibition of tumor growth was observed only for the shGALA-MEND and no somatic or hepatic toxicity was observed. Given the above data, this peptide-modified delivery system, a shGALA-MEND has great potential for the systemic delivery of therapeutic siRNA aimed at cancer therapy.

Keywords: Liposome; Membrane fusion; Peptide; siRNA delivery; Multi-functional envelop type nano device (MEND)

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