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Biomaterials (v.31, #35)

Editorial board (pp. ofc).

A strategy for precision engineering of nanoparticles of biodegradable copolymers for quantitative control of targeted drug delivery by Yutao Liu; Kai Li; Bin Liu; Si-Shen Feng (pp. 9145-9155).
Research on quantitative control of targeting effect for the drug delivery system of ligand-conjugated nanoparticles of biodegradable polymers is at the cutting edge in the design of drug delivery device. In this work, we developed a post-conjugation strategy, which makes the ligand conjugation after the preparation of the drug-loaded nanoparticles of two copolymers blend. We synthesized the PLGA-PEG copolymer with PEG functioning as the linker molecule needed for herceptin conjugation. Docetaxel-loaded nanoparticles of the PLGA-PEG/PLGA copolymer blend were prepared by the nanoprecipitation method. Anti-HER2 antibody (heceptin), which targets the breast cancer cells of HER2 receptor overexpression, was conjugated on the drug-loaded PLGA-PEG/PLGA nanoparticles for sustained, controlled and targeted delivery of docetaxel. We demonstrated that the targeting effect can be quantitatively controlled by two ways, i.e. (1) adjusting the copolymer blend ratio of the nanoparticle matrix, which showed within the range of 20% PLGA/PEG in the copolymer blend a linear relation with the ligand density on the nanoparticle surface, and (2) adjusting the herceptin feed molar ratio to NH2 in the linker molecules appearing on the nanoparticle surface, which also showed a linear relation. Compared with the pre-conjugation strategy developed recently in the literature, in which the ligand was firstly conjugated onto the PLGA-PEG copolymer before preparation of the nanoparticles of the PLGA-PEG/PLGA copolymer blend, the post-conjugation strategy provides more efficient use of the ligand and protects its bioactivity in the nanoparticle preparation process, thus resulting in much better performance in drug targeting, which was assessed in vitro with SK-BR-3 breast cancer cells of HER2 receptor overexpression and MCF7 breast cancer cells of HER2 receptors moderate expression.

Keywords: Biodegradable copolymers; Cancer nanotechnology; Docetaxel; Drug targeting; Herceptin; Nanomedicine

Notched fatigue behavior of PEEK by Michacl C. Sobieraj; James E. Murphy; Jennifer G. Brinkman; Steve M. Kurtz; Clare M. Rimnac (pp. 9156-9162).
Poly(ether-ether-ketone) (PEEK) has been used as a load bearing orthopaedic implant material with clinical success. All of the orthopaedic applications contain stress concentrations (notches) in their design; however, little work has been done to examine the fatigue behavior of PEEK in the presence of a notch. This work examines both stress-life (S–N) fatigue behavior and the fracture behavior of unfilled PEEK under tension–tension loading in circumferentially grooved round bar specimens with different elastic stress concentration factors. It was found that the majority of the loading was elastic in nature, and that there was only a small portion on the lifetime where there was a detectable change in structural behavior prior to gross fracture. Fractographic analysis via SEM further elucidated the potential fracture micromechanisms. Additional analysis was conducted to estimate the percent of the lifetime spent in crack initiation vs. propagation, and it was found that the specimens spent the majority of the time in the crack initiation phase.

Keywords: Orthopaedic implants; Notches; Fatigue; PEEK; Notched LEFM

A comparison of the tissue response to chronically implanted Parylene-C-coated and uncoated planar silicon microelectrode arrays in rat cortex by Brent D. Winslow; Michael B. Christensen; Wen-Kuo Yang; Florian Solzbacher; Patrick A. Tresco (pp. 9163-9172).
In this study we employed a quantitative immunohistochemical approach to compare the brain tissue response to planar silicon microelectrode arrays that were conformally coated with Parylene-C to uncoated controls at 2, 4, and 12 weeks following implantation into the cortex of adult male Sprague-Dawley rats. We did not find any difference in the relative intensity or the spatial distribution of neuronal or glial markers over the indwelling period, even though Parylene-C-coated substrates supported significantly less cell attachment, indicating that the foreign body response to planar silicon microelectrode arrays has little to do with the composition or decomposition of the silicon electrode. Moreover, our results suggest that changes in microelectrode surface chemistry do not have a strong influence on the cytoarchitectural changes that accompany the brain foreign body response to planar silicon microelectrode arrays. Our quantitative comparison over the indwelling period does not support progressive increases in astrocyte encapsulation and/or progressive neuronal loss in the recording zone as dominant failure mechanisms of the type of chronic recording device. Finally, we found evidence of two potentially new failure mechanisms that were associated with CD68 immunoreactivity including demyelination of adjacent neurons and BBB breakdown surrounding implanted electrodes at long indwelling times.

Keywords: Electrode; Inflammation; Neural prosthesis; Foreign body response; Surface modification

The acceleration of implant osseointegration by liposomal Wnt3a by Antoine Popelut; Scott M. Rooker; Philipp Leucht; Marie Medio; John B. Brunski; Jill A. Helms (pp. 9173-9181).
The strength of a Wnt-based strategy for tissue regeneration lies in the central role that Wnts play in healing. Tissue injury triggers local Wnt activation at the site of damage, and this Wnt signal is required for the repair and/or regeneration of almost all tissues including bone, neural tissues, myocardium, and epidermis. We developed a biologically based approach to create a transient elevation in Wnt signaling in peri-implant tissues, and in doing so, accelerated bone formation around the implant. Our subsequent molecular and cellular analyses provide mechanistic insights into the basis for this pro-osteogenic effect. Given the essential role of Wnt signaling in bone formation, this protein-based approach may have widespread application in implant osseointegration.

Keywords: Wnt; Beta catenin; Bone; Osteoblast; Liposome; Endosteum

A combinatorial screening of human fibroblast responses on micro-structured surfaces by Kristian Kolind; Alireza Dolatshahi-Pirouz; Jette Lovmand; Finn Skou Pedersen; Morten Foss; Flemming Besenbacher (pp. 9182-9191).
Biomaterial surfaces structured with topographical features have been predicted to play an important role in the next generation of biomedical implants. Specific trends with regard to the influence of the topographical effect on cellular behavior are however challenging to establish due to differences in the topographical features and geometries in the various studies. Here, we demonstrate the use of a highly versatile combinatorial screening approach to identify the effect of 169 distinct surface topographies, consisting of pillars, on fibroblast proliferation and mechanical response. Altering the inter-pillar gap size of the structures revealed a significant change in fibroblast proliferation and identified obvious stress-induced changes in the cytoskeleton and focal adhesion morphology. Larger (4–6 μm) inter-pillar gap sizes reduced fibroblast proliferation and elicited a strong elongation leading to a disruption of the actin cytoskeleton anchored primarily to focal adhesions located between the pillars. Smaller (1–2 μm) inter-pillar gap sizes, on the contrary, caused the fibroblasts to proliferate comparable to cells on a non-structured surface with cells having a clear actin cytoskeleton attached to focal adhesions located mostly on top of the pillars. The approach reveals a strong correlation between the exact topographical periodicities and cellular responses such as cell proliferation, cell morphology and focal adhesion.

Keywords: Fibroblast; Cell proliferation; Surface topography; Microstructure; Combinatorial screening

The relationship between collagen scaffold cross-linking agents and neutrophils in the foreign body reaction by Qingsong Ye; Martin C. Harmsen; Marja J.A. van Luyn; Ruud A. Bank (pp. 9192-9201).
In order to get more insight into the role of neutrophils on the micro-environment and consequently on macrophages in the foreign body reaction in mice, we investigated the fate of the two differently cross-linked dermal sheep collagen disks (glutaraldehyde = GDSC, hexamethylenediisocyanate = HDSC) in mice implanted in one anatomical location, namely subcutaneously. In GDSC massive infiltration of neutrophils is seen at day 2 and day 21, whereas in HDSC only minor infiltration is seen at day 2. The presence of neutrophils coincided with high levels of IFN-γ, a cytokine that activates macrophages. Major differences were seen in degradation rate of the two disks: GDSC was almost completely degraded after 28 days, whereas HDSC remained intact. Degradation of GDSC occurred through collagenolytic activity and phagocytosis by macrophages. Phagocytosis was observed at day 2 and day 21. IL-13 was only observed in HDSC, and this resulted in the presence of giant cells in HDSC. These giant cells produced IL-10, that promoted TIMP-1 expression and that inhibits collagenolytic and phagocytic activity. We conclude that the function of macrophages in mice is largely influenced by differences in micro-environment induced by GDSC and HDSC and that the presence/absence of neutrophils play a major role in the shaping of this micro-environment.

Keywords: Matrix metalloproteinase; Foreign body reaction; Giant cell formation; Phagocytosis; Interferon-gamma; Neutrophils

Biological synthesis of tooth enamel instructed by an artificial matrix by Zhan Huang; Christina J. Newcomb; Pablo Bringas Jr.; Samuel I. Stupp; Malcolm L. Snead (pp. 9202-9211).
The regenerative capability of enamel, the hardest tissue in the vertebrate body, is fundamentally limited due to cell apoptosis following maturation of the tissue. Synthetic strategies to promote enamel formation have the potential to repair damage, increase the longevity of teeth and improve the understanding of the events leading to tissue formation. Using a self-assembling bioactive matrix, we demonstrate the ability to induce ectopic formation of enamel at chosen sites adjacent to a mouse incisor cultured in vivo under the kidney capsule. The resulting material reveals the highly organized, hierarchical structure of hydroxyapatite crystallites similar to native enamel. This artificially triggered formation of organized mineral demonstrates a pathway for developing cell fabricated materials for treatment of dental caries, the most ubiquitous disease in man. Additionally, the artificial matrix provides a unique tool to probe cellular mechanisms involved in tissue formation further enabling the development of tooth organ replacements.

Keywords: RGDS peptide; Self-assembly; Peptide amphiphile; Extracellular matrix; Epithelial cell; Cell activation

The promotion of neural regeneration in an extreme rat spinal cord injury model using a collagen scaffold containing a collagen binding neuroprotective protein and an EGFR neutralizing antibody by Qianqian Han; Wei Jin; Zhifeng Xiao; Hongbin Ni; Jinhuan Wang; Jie Kong; Jun Wu; Weibang Liang; Lei Chen; Yannan Zhao; Bing Chen; Jianwu Dai (pp. 9212-9220).
In the treatment of spinal cord injury, implantation of scaffolding biomaterials and the addition of neuroprotective factors will promote neural regeneration. It has been demonstrated in our previous work that linear ordered collagen scaffold (LOCS) will bridge neural regeneration after the injury of spinal cord hemisection, and BDNF fused with a collagen binding domain (CBD-BDNF) can bind to collagen specifically to exert the neuroprotective effect. Besides neuroprotective factors, the lack of axon regeneration of the injured spinal cord has been attributed partially to regeneration inhibitors such as myelin associated proteins and chondroitin sulfate proteoglycans (CSPGs). Epidermal growth factor receptor (EGFR) activation is downstream of the signaling pathways of these inhibitors. Here, the monoclonal antibody, 151IgG that inhibits signaling of EGFR was used to neutralize EGFR. 151IgG was cross-linked to LOCS and CBD-BDNF bound to LOCS to make a triple-functional biomaterial for neural regeneration (bridging, prompting growth and neutralizing growth inhibitors). This triple-functional device was tested in a 6 mm transected SCI model. Results showed that this collagen scaffold with the addition of 151IgG and CBD-BDNF provided effective bridging and stimulation effects for neural regeneration, recovery of electrical transmission of synapses and preventing the formation of glial scars in the extreme transected rat SCI model.

Keywords: Collagen; EGFR neutralizing antibody; Spinal cord injury; Nerve regeneration

Using growth factor arrays and micropatterned co-cultures to induce hepatic differentiation of embryonic stem cells by Nazgul Tuleuova; Ji Youn Lee; Jennifer Lee; Erlan Ramanculov; Mark A. Zern; Alexander Revzin (pp. 9221-9231).
The success in driving embryonic stem cells towards hepatic lineage has been confounded by the complexity and cost of differentiation protocols that employ large quantities of expensive growth factors (GFs). Instead of supplementing culture media with soluble GFs, we investigated cultivation and differentiation of mouse embryonic stem cells (mESCs) on printed arrays of GFs. Hepatocyte growth factor (HGF), basic fibroblast growth factor (bFGF) and bone morphogenetic protein (BMP4) were mixed in solution with fibronectin and collagen (I) and then printed onto silane-modified glass slides to form 500 μm diameter protein spots. mESCs were cultured on top of GF spots for up to 12 days and analyzed by RT-PCR and immunostaining at different time points. The stem cells residing on HGF-containing combinations of GFs exhibited requisite features of hepatic differentiation including pronounced loss in pluripotency (Oct4), transient (up and down) expression of endoderm (Sox17) and upregulation of early hepatic markers – albumin and alpha-fetoprotein. The hepatic differentiation was enhanced further by adding hepatic stellate cells to surfaces that already contained mESCs on GF spots. A combination of co-culture with non-parenchymal liver cells and the optimal GF stimulation was found to induce endoderm and hepatic phenotype earlier and to a much greater extent than the GF arrays or micropatterned co-cultures used individually. While this paper investigated hepatic differentiation of mouse ESCs, our findings and stem cell culture approaches are likely to be relevant for human ESC cultivation. Overall, the platform combining printed GF arrays and heterotypic co-cultures will be broadly applicable for identifying the composition of the microenvironment niche for ESC differentiation into various tissue types.

Keywords: Growth factor arrays; Micropatterned co-cultures; Hepatic differentiation; Embryonic stem cells

The healing of bony defects by cell-free collagen-based scaffolds compared to stem cell-seeded tissue engineered constructs by Frank G. Lyons; Amir A. Al-Munajjed; Stephen M. Kieran; Mary E. Toner; Ciara M. Murphy; Garry P. Duffy; Fergal J. O’Brien (pp. 9232-9243).
One of the key challenges in tissue engineering is to understand the host response to scaffolds and engineered constructs. We present a study in which two collagen-based scaffolds developed for bone repair: a collagen–glycosaminoglycan (CG) and biomimetic collagen-calcium phosphate (CCP) scaffold, are evaluated in rat cranial defects, both cell-free and when cultured with MSCs prior to implantation. The results demonstrate that both cell-free scaffolds showed excellent healing relative to the empty defect controls and somewhat surprisingly, to the tissue engineered (MSC-seeded) constructs. Immunological analysis of the healing response showed higher M1 macrophage activity in the cell-seeded scaffolds. However, when the M2 macrophage response was analysed, both groups (MSC-seeded and non-seeded scaffolds) showed significant activity of these cells which are associated with an immunomodulatory and tissue remodelling response. Interestingly, the location of this response was confined to the construct periphery, where a capsule had formed, in the MSC-seeded groups as opposed to areas of new bone formation in the non-seeded groups. This suggests that matrix deposited by MSCs during in vitro culture may adversely affect healing by acting as a barrier to macrophage-led remodelling when implanted in vivo. This study thus improves our understanding of host response in bone tissue engineering.

Keywords: Bone tissue engineering; Collagen; Scaffold; Mesenchymal stem cells; Host immune response; Macrophage

Bioelectrochemical control of neural cell development on conducting polymers by Jorge E. Collazos-Castro; José L. Polo; Gabriel R. Hernández-Labrado; Vanesa Padial-Cañete; Concepción García-Rama (pp. 9244-9255).
Electrically conducting polymers hold promise for developing advanced neuroprostheses, bionic systems and neural repair devices. Among them, poly(3, 4-ethylenedioxythiophene) doped with polystyrene sulfonate (PEDOT:PSS) exhibits superior physicochemical properties but biocompatibility issues have limited its use. We describe combinations of electrochemical and molecule self-assembling methods to consistently control neural cell development on PEDOT:PSS while maintaining very low interfacial impedance. Electro-adsorbed polylysine enabled long-term neuronal survival and growth on the nanostructured polymer. Neurite extension was strongly inhibited by an additional layer of PSS or heparin, which in turn could be either removed electrically or further coated with spermine to activate cell growth. Binding basic fibroblast growth factor (bFGF) to the heparin layer inhibited neurons but promoted proliferation and migration of precursor cells. This methodology may orchestrate neural cell behavior on electroactive polymers, thus improving cell/electrode communication in prosthetic devices and providing a platform for tissue repair strategies.

Keywords: Conducting polymers; PEDOT:PSS; Self-assembled multilayers; Cell culture; Electrochemistry; Neural cells

The role of transglutaminase 2 and osteopontin in matrix protein supplemented microencapsulation of marrow stromal cells by Nazanin Hakimzadeh; Duncan J. Stewart; David W. Courtman (pp. 9256-9265).
Previous studies reported that matrix protein supplementation (fibronectin/fibrinogen, FN/FG) of agarose gel microcapsules enhances survival and target tissue retention of syngeneic rat marrow stromal cells (MSCs). We hypothesized that additional supplementation of microcapsules with osteopontin (OPN) and transglutaminase 2 (TG2) would enhance cell survival, while stabilizing the provisional matrix. Using monomeric OPN or OPN polymerized with TG2, we examined human MSC adhesion, morphology, focal contact formation and apoptosis. Polymeric OPN with TG2 induced greater adhesion than monomeric OPN (84.5 ± 10.7 vs. 44.3 ± 10.0 cells/field), and also significantly enhanced focal contact formation (351.5 ± 21.2 vs. 45.6 ± 17.6 focal contact sites/cell) and cell spreading (2.7 × 103 ± 0.20 × 103 μm2 vs. 1.2 × 103 ± 0.26 × 102 μm2) while preserving MSC pluripotency. Microcapsules supplemented with FN/FG, polymeric OPN and TG2 demonstrated significantly less apoptotic cells than FN/FG microcapsules (14.0 ± 2.34% vs. 28.2 ± 3.22%). Reduced apoptosis was attributed to matrix stabilization by TG2 and the synergistic activity of matrix proteins. It is anticipated that this enhanced survival will maximize the therapeutic potential of MSCs.

Keywords: Cell therapy; Mesenchymal stem cells (MSCs); Microencapsulation; Extracellular matrix (ECM); Osteopontin; Transglutaminase 2

In situ thermal gelling polypeptide for chondrocytes 3D culture by Bo Gyu Choi; Min Hee Park; So-Hye Cho; Min Kyung Joo; Hye Jin Oh; Eun Hye Kim; Kwideok Park; Dong Keun Han; Byeongmoon Jeong (pp. 9266-9272).
In the search for a cell-instructive or cell-interactive artificial extracellular matrix, synthetic hydrogels have been extensively investigated to apply three-dimensional (3D) cell culture and tissue engineering. Here, we are reporting a reverse thermal gellingl/dl-polyalanine block copolymer aqueous solution for chondrocyte 3D culture. The polymer aqueous solution undergoes sol-to-gel transition as the temperature increases, thus forming a 3D cell encapsulating scaffold in situ at 37 °C. In particular, the fraction of the β-sheet structure of the polyalanine dictated the population and thickness of fibrous nanostructure of the hydrogel, which in turn affected the proliferation and protein expression of the encapsulated chondrocytes. As an injectable tissue engineering system of chondrocytes, very promising results were confirmed for nude mice, using the current polypeptide aqueous solution. This paper not only provides important clues in designing an artificial extracellular matrix but also proves the significance of thermal gelling polypeptide as a minimally-invasive tissue engineering scaffold.

Keywords: Secondary structure; Peptide; Thermally responsive material; Hydrogel; Chondrocyte; Cell culture

Stromal cell-induced immune regulation in a transplantable lymphoid-like cell constructs by Yael Kaminer-Israeli; Jenny Shapiro; Smadar Cohen; Alon Monsonego (pp. 9273-9284).
Engineering of cell-based constructs for treating a variety of immune-related diseases by local transplantation of the cells in a pre-designed matrix is an emerging therapeutic approach, which can potentially reduce the side effects associated with systemic cell injection. Stromal cells have been shown to exert immunosuppressive properties and thus can be exploited for autoimmune regulation and cell transplantation. Here, we demonstrate the fabrication of a stromal cell-based construct, which serves as a lymphoid-like organ with immune regulatory characteristics. In the proposed system, stromal cells are co-seeded with dendritic cells (DC) in a macro-porous alginate scaffold containing the encephalitogenic myelin-derived peptide, proteolipid protein (PLP). We demonstrate that the presence of stromal cells attenuates DC maturation upon lipopolysaccharide stimulus. In vitro, we show that while the migration of pathogenic PLP-specific T cells to construct cultivated with or without stromal cells does not differ, their activation and proliferation are significantly suppressed in the presence of stromal cells. Upon in vivo transplantation, under the kidney capsule of mice, the pathogenic activation and proliferation of T cells which were drawn into the construct were suppressed in the co-seeded constructs. This system thus serves as a lymphoid-like organ with regulatory characteristics, which can be applied for local tolerance induction, for application in cell transplantations as well as autoimmune diseases.

Keywords: Stromal cells; Dendritic cells; Alginate scaffold; Immune regulation

Staphylococcus aureus resistance on titanium coated with multivalent PEGylated-peptides by Xiaojuan Khoo; George A. O’Toole; Shrikumar A. Nair; Brian D. Snyder; Daniel J. Kenan; Mark W. Grinstaff (pp. 9285-9292).
Bacterial infections can have adverse effects on the efficacy, lifetime and safety of an implanted device and are the second most commonly attributed cause of orthopedic implant failure. We have previously shown the assembly of PEGylated titanium-binding peptides (TBPs) on Ti to obtain a bacteriophobic surface coating that can effectively resist protein adsorption and Staphylococcus aureus ( S. aureus) adhesion. In the present study, we examine the effect of multiple TBP repeats on coating performance in vitro. Mono, di, and tetravalent peptides were synthesized and assessed for binding affinity and serum stability. PEGylated analogs were prepared and evaluated for their effect on S. aureus attachment and biofilm formation. Coating performance improved with the number of TBP repeats, with the tetravalent coating,TBP4PEG, showing the best performance in all assays. In particular,TBP4PEG forms a serum-resistant surface coating capable of preventing S. aureus colonization and subsequent biofilm formation. These results further support the role that multivalency can play in the development of improved surface coatings with enhanced stabilities and efficacy for in vivo clinical use.

Keywords: Peptide; Surface modification; Bacteria; Biofilm; Implant; Biomaterial

The use of BMP-2 coupled – Nanosilver-PLGA composite grafts to induce bone repair in grossly infected segmental defects by Zhong Zheng; Wei Yin; Janette N. Zara; Weiming Li; Jinny Kwak; Rachna Mamidi; Min Lee; Ronald K. Siu; Richard Ngo; Joyce Wang; Doug Carpenter; Xinli Zhang; Benjamin Wu; Kang Ting; Chia Soo (pp. 9293-9300).
Healing of contaminated/infected bone defects is a significant clinical challenge. Prevalence of multi-antibiotic resistant organisms has renewed interest in the use of antiseptic silver as an effective, but less toxic antimicrobial with decreased potential for bacterial resistance. In this study, we demonstrated that metallic nanosilver particles (with a size of 20–40nm)-poly(lactic- co-glycolic acid) (PLGA) composite grafts have strong antibacterial properties. In addition, nanosilver particles-PLGA composite grafts did not inhibit adherence, proliferation, alkaline phosphatase activity, or mineralization of ongrowth MC3T3-E1 pre-osteoblasts compared to PLGA controls. Furthermore, nanosilver particles did not affect the osteoinductivity of bone morphogenetic protein 2 (BMP-2). Infected femoral defects implanted with BMP-2 coupled 2.0% nanosilver particles-PLGA composite grafts healed in 12 weeks without evidence of residual bacteria. In contrast, BMP-2 coupled PLGA control grafts failed to heal in the presence of continued bacterial colonies. Our results indicate that nanosilver of defined particle size is bactericidal without discernable in vitro and in vivo cytotoxicity or negative effects on BMP-2 osteoinductivity, making it an ideal antimicrobial for bone regeneration in infected wounds.

Keywords: Bone repair; Antimicrobial; Nanosilver particle; Bone morphogenetic protein 2 (BMP-2)

Tailored sizes of constrictive external vein meshes for coronary artery bypass surgery by Thomas Franz; Paul Human; Stephan Dobner; B. Daya Reddy; Melanie Black; Helen Ilsley; Michael F. Wolf; Deon Bezuidenhout; Lovendran Moodley; Peter Zilla (pp. 9301-9309).
External mesh constriction of vein grafts was shown to mitigate intimal hyperplasia by lowering circumferential wall stress and increasing fluid shear stress. As under-constriction leaves vein segments unsupported and thus prone to neointimal proliferation while over-constriction may cause wall folding optimal mesh sizing holds a key to clinical success. Diameter fluctuations and the occurrence of wall folding as a consequence of external constriction with knitted Nitinol meshes were assessed in saphenous vein grafts from 100 consecutive coronary artery bypass (CABG) patients. Subsequently, mesh dimensions were identified that resulted in the lowest number of mesh sizes for all patients either guaranteeing tight continual mesh contact along the entire graft length (stipulation A) or preventing wall folding (stipulation B). A mathematical data classification analysis and a statistical single-stage partitioning approach were independently applied alternatively prioritizing stipulation A or B. Although the risk of folding linearly increased when constriction exceeded 24.6% (Chi squared test p = 0.0004) the actual incidence of folding (8.6% of veins) as well as the degree of lumenal encroachment (6.2 ± 2.1%) were low. Folds were always single, narrow longitudinal formations (height: 23.3 ± 4.0% of inner diameter/base: 16.6 ± 18.1% of luminal circumference). Both analytical methods provided an optimum number of 4 mesh sizes beyond which no further advantage was seen. While the size ranges recommended by both methods assured continual tight mesh contact with the vein the narrower range suggested by the mathematical data classification analysis (3.0–3.7 mm) put 20.6 ± 12.5% of length in 69% of veins at risk of folding as opposed to 21.3 ± 25.9% being at risk in the wider size range (3.0–4.2 mm) suggested by the statistical partitioning approach. Four mesh sizes would provide uninterrupted mesh contact in 98% of vein grafts in CABG procedures with only 26% of their length being at risk of relatively mild wall folding.

Keywords: Vein grafts; External support; Coronary artery bypass graft; Luminal folding; Luminal constriction

Self-assembled fluorescent magnetic nanoprobes for multimode-biomedical imaging by Eun-Kyung Lim; Jaemoon Yang; Colin P.N. Dinney; Jin-Suck Suh; Yong-Min Huh; Seungjoo Haam (pp. 9310-9319).
We fabricated multimode nanoprobes for acquisition of biological information at different object levels, i.e., in vivo detection and ex vivo validation for characterizing tumor angiogenesis. Fluorescent magnetic nanoprobes (FMNPs) were synthesized by using amphiphilic pyrenyl polyethylene glycol (Py-PEG) and superparamagnetic MnFe2O4 nanocrystals (MNCs). Py-PEG, which is synthesized by conjugation of hydrophilic PEG with hydrophobic and fluorescent 1-pyrenebutyric acid through an esterification process, is capable of self-assembly and maintaining a high UV fluorescent intensity in aqueous phase. Py-PEG can be used as a fluorescent surfactant that simultaneously and efficiently encapsulates MNCs to exhibit fluorescent and magnetic properties as well as maintaining high water-solubility. Consequently, we proved that our biologically non-toxic FMNPs were prominent multimode imaging probes by showing not only excellent MR sensitivity but also high illumination intensity with strong signal strength under short exposure time of UV light from the extensive imaging studies of in vitro/vivo and ex vivo using orthotopic and xenograft mice models.

Keywords: Nanoprobe; Magnetic resonance imaging; Multimode; Fluorescent

Heparinized chitosan/poly(γ-glutamic acid) nanoparticles for multi-functional delivery of fibroblast growth factor and heparin by Deh-Wei Tang; Shu-Huei Yu; Yi-Cheng Ho; Fwu-Long Mi; Pi-Li Kuo; Hsing-Wen Sung (pp. 9320-9332).
To improve blood supply following ischemic injury, angiogenic factors such as fibroblast growth factor (bFGF) that stimulate new blood vessel formation have been used for therapeutic angiogenesis in ischemic tissues. In this study, heparin-functionalized chitosan (CS)/poly(γ-glutamic acid) (γ-PGA) nanoparticles (HP-CS/γ-PGA nanoparticles) were prepared for multi-functional delivery of basic fibroblast growth factor (bFGF) and heparin. The mean particle sizes and bFGF loading efficiency increased with the increase of functionalized heparin contents. The HP-CS/γ-PGA nanoparticles were pH-sensitive that could sustain bFGF release at pH ? 6.7 (simulate the pH of ischemia tissue) and were rapidly disintegrated at pH 7.4 (simulate the pH of repaired tissue). Sustained release of bFGF from the nanoparticles enhanced the proliferation of human foreskin fibroblast cells (HFF) and angiogenic tube formation by human umbilical vein endothelial cells (HUVEC), suggesting the retaining of bFGF mitogenic activity. Heparin, a traditionally used anticoagulant, could release from the disintegrated nanoparticles to maintain the anti-factor Xa activity in blood plasma, after increasing the pH value from 6.6 to 7.4. The nanocarriers for mutil-functional delivery of bFGF and heparin developed in this study may be a potential therapeutic method for enhancing ischemic tissue regeneration and preventing blood vessel rethrombosis.

Keywords: Heparin-functionalized; Chitosan; γ-PGA; Nanoparticles; bFGF

Internalization and kinetics of nuclear migration of protein-only, arginine-rich nanoparticles by Esther Vázquez; Rafael Cubarsi; Ugutz Unzueta; Mónica Roldán; Joan Domingo-Espín; Neus Ferrer-Miralles; Antonio Villaverde (pp. 9333-9339).
Understanding the intracellular trafficking of nanoparticles internalized by mammalian cells is a critical issue in nanomedicine, intimately linked to therapeutic applications but also to toxicity concerns. While the uptake mechanisms of carbon nanotubes and polymeric particles have been investigated fairly extensively, there are few studies on the migration and fate of protein-only nanoparticles other than natural viruses. Interestingly, protein nanoparticles are emerging as tools in personalized medicines because of their biocompatibility and functional tuneability, and are particularly promising for gene therapy and also conventional drug delivery. Here, we have investigated the uptake and kinetics of intracellular migration of protein nanoparticles built up by a chimerical multifunctional protein, and functionalized by a pleiotropic, membrane-active (R9) terminal peptide. Interestingly, protein nanoparticles are first localized in endosomes, but an early endosomal escape allows them to reach and accumulate in the nucleus (but not in the cytoplasm), with a migration speed of 0.0044 ± 0.0003 μm/s, ten-fold higher than that expected for passive diffusion. Interestingly, the plasmatic, instead of the nuclear membrane is the main cellular barrier in the nuclear way of R9-assisted protein-only nanoparticles.

Keywords: Nanoparticle; Genetic engineering; Protein; Biocompatibility; Drug delivery

Long circulation and cytotoxicity of PEGylated gemcitabine and its potential for the treatment of pancreatic cancer by Mallaredy Vandana; Sanjeeb K. Sahoo (pp. 9340-9356).
Gemcitabine [2′, 2′-difluoro-2′-deoxycytidine (dFdC)] is a low molecular weight, deoxycytidine analog inhibiting cellular DNA synthesis. Currently, it is the frontline drug approved by Food and Drug Administration (FDA) for the treatment of pancreatic cancer. However, efforts to use gemcitabine as an anti-cancer agent have been limited by its short circulation time and rapid metabolism that reflects in low tumor uptake and intracellular action. Polymer–drug conjugates, in this regard have spawned an approach to improve the cytotoxicity efficiency and bioavailability of gemcitabine by chemical modification. The present study describes the synthesis of a water soluble formulation of PEGylated gemcitabine characterized by FT IR,1H NMR and RP-HPLC chromatography. The PEGylated gemcitabine has a prolonged circulation time in plasma as studied in an animal model. This eventually caused a marked improvement in the cytotoxicity and apoptosis-inducing activity in pancreatic cancer cell lines (MIA PaCa 2 and PANC 1). Hence, these findings demonstrate the PEGylated gemcitabine is a desirable approach for therapy by intravenous administration. Successful clinical application of this approach can significantly contribute to the treatment of pancreatic cancer.

Keywords: Gemcitabine; Pancreatic cancer; PEGylated gemcitabine; Bioavailability; Apoptosis; Cytotoxicity

Amphoteric hyaluronic acid derivative for targeting gene delivery by Jing Yao; Ying Fan; Ronghui Du; Jianping Zhou; Yun Lu; Wei Wang; Jin Ren; Xiaojing Sun (pp. 9357-9365).
The study aimed to develop an amphoteric hyaluronic acid (HA) derivative with polyethyleneimine (PEI) chains (HAP) for gene delivery to overcome the disadvantages of PEI as gene carrier including the cytotoxicity caused by excess of positive charge, non-special interaction and aggregation in the blood, and non-target gene delivery. The HAP was synthesized by an imine reaction between periodate-oxidized HA and PEI. The HAP/DNA complex was prepared, and its characterization was investigated. The size of complex with higher molecular weight HA in PBS was about 200 nm at optimal charge ratio. No apparent aggregation among the particles was observed. The HAPs also showed high protection of DNA from nuclease, better dissociation of DNA from the complex and lower cytotoxicity. It also exhibited higher transfection efficiency in HepG2 cells than the PEI/DNA complex. Among all complexes, the HAP50/DNA complex was especially found to be most efficient, yielding comparable transfection efficiency with that of Lipofectamine/DNA lipoplexes. Moreover, the HAP-IR820 obviously accumulated in tumor after i.v. administration as compared to the PEI-IR820, which indicated that the HAP could assist the DNA targeting to the tumor. Therefore, HAP should be a promising non-viral gene vector.

Keywords: Targeting gene delivery; Hyaluronic acid; Polyethyleneimine; Transfection; p53

Multilayered polyplexes with the endosomal buffering polycation in the core and the cell uptake-favorable polycation in the outer layer for enhanced gene delivery by Jin-He Ke; Tai-Horng Young (pp. 9366-9372).
In the present study, quaternary polyplexes were prepared by sequential addition of polycations (polyethylenimine (PEI) or poly ( N-(8-aminooctyl)-acrylamide) (P8Am)) for loading pDNA into the core polyplexes and poly (acrylic acid) (PAA) for reversing charges to deposit additional polycation (PEI or P8Am) layer. It was found the cytotoxicity and cellular uptake expression of PEI core polyplexes could be improved by coating a cell uptake-favorable P8Am layer. Conversely, P8Am could not facilitate endosomal release through the proposed proton sponge effect so the PEI core was required for the P8Am-coated quaternary polyplexes to ensure efficient transfection. Consequently, an efficient and safe non-viral gene vehicle was constructed by layer-by-layer deposition, using alternate polyanion and polycation with required functionalities to overcome the obstacles met in the process of transfection. Maximum transfection activity with minimal toxicity was observed when the quaternary polyplex of pDNA/PEI/PAA/P8Am was prepared at a weight ratio of 1/1.5/3/5. Conversely, the same composition in different position such as the cell-favorable P8Am core was externally deposited with the endosome lytic moiety, PEI showed high toxicity and low efficiency. This indicates the pDNA/PEI/PAA/P8Am sequence for a quaternary polyplex is as important as the functional polymer selection for designing safe and reliable gene delivery vehicles. We demonstrate here that gene delivery efficiency may be improved by increasing the uptake level and the endosomal buffering release through an additional layer of cell uptake-favorable polycations associated with the core polycations possessing endosomal release ability.

Keywords: Gene therapy; Gene vehicle; Polyelectrolyte multilayer; Polycation

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