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Biomaterials (v.32, #19)

Editorial board (pp. ifc).

The effect of CD47 modified polymer surfaces on inflammatory cell attachment and activation by Stanley J. Stachelek; Matthew J. Finley; Ivan S. Alferiev; Fengxiang Wang; Richard K. Tsai; Edward C. Eckells; Nancy Tomczyk; Jeanne M. Connolly; Dennis E. Discher; David M. Eckmann; Robert J. Levy (pp. 4317-4326).
CD47 is a transmembrane protein that is a marker of “self”. CD47 binding to its cognate receptor in leukocytes and macrophages, signal-regulatory protein alpha (SIRPα), causes inhibition of inflammatory cell attachment. We hypothesized that immobilization of recombinant CD47 on polymeric surfaces would reduce inflammation. Recombinant CD47 was appended to polyvinyl chloride (PVC) or polyurethane (PU) surfaces via photoactivation chemistry. Cell culture studies showed that CD47 immobilization significantly reduced human neutrophil (HL-60) and human monocyte derived macrophage (MDM) (THP-1) attachment to PVC and PU respectively. A neutralizing antibody, directed against SIRPα, inhibited THP-1 and HL-60 binding to PU and PVC surfaces respectively. This antibody also increased the level of SIRPα tyrosine phosphorylation, thereby indicating a direct role for SIRPα mediated signaling in preventing inflammatory cell attachment. Studies using human blood in an ex vivo flow-loop showed that CD47 modified PVC tubing significantly reduced cell binding and neutrophil activation compared to unmodified tubing or poly-2-methoxy-ethylacrylate (PMEA) coated tubing. In ten-week rat subdermal implants, CD47 functionalized PU films showed a significant reduction in markers of MDM mediated oxidative degradation compared to unmodified PU. In conclusion, CD47 functionalized surfaces can resist inflammatory cell interactions both in vitro and in vivo.

Keywords: Polyurethane; Cell adhesion; Biomimetic material; Polyvinyl chloride; Surface modification


Cell behavior on protein matrices containing laminin α1 peptide AG73 by Yuji Yamada; Fumihiko Katagiri; Kentaro Hozumi; Yamato Kikkawa; Motoyoshi Nomizu (pp. 4327-4335).
Collagen has been widely used for tissue engineering. Here, we applied bioactive laminin-derived peptides as an additive for collagen, laminin-111, and fibronectin matrices resulting in peptide/collagen, peptide/laminin-111, and peptide/fibronectin matrices. Several syndecan-binding peptides, including AG73 (RKRLQVQLSIRT), enhanced the cell attachment activity of collagen matrices. AG73 synergistically enhanced not only cell attachment but also cell spreading on collagen matrices. AG73 also enhanced integrin-binding to the collagen matrices, including organization of actin stress fibers and promotion of Tyr397-focal adhesion kinase (FAK) phosphorylation. Additionally, AG73 enhanced neurite outgrowth on collagen matrices. These results suggest that the integrin-mediated biological activity of collagen matrices is synergistically enhanced by the syndecan-mediated cellular function of AG73. Further, cell attachment and spreading activity of laminin-111 and fibronectin matrices was also synergistically enhanced by AG73. The syndecan-binding peptides are useful to enhance the integrin-mediated biological activities of extracellular matrix (ECM) proteins, such as collagen, laminin-111, and fibronectin. The peptide/matrix mixed method is a new concept for biomaterial fabrication and has the potential for wide use in cell and tissue engineering.

Keywords: Peptide; Collagen; Integrin; ECM(extra cellular matrix); Laminin; FibroconectinAbbreviations; FAK; focal adhesion kinase; ECM; extracellular matrix; Fmoc; 9-fluorenylmethoxycarbonyl; HDFs; human dermal fibroblasts; DMEM; Dulbecco’s modified Eagle’s medium; FBS; fetal bovine serum; BSA; bovine serum albumin; EDTA; ethylenediaminetetraacetic acid; PBS; phosphate-buffered saline; DAPI; 4,6-diamidino-2-phenylindole; SDS; sodium dodecyl sulfate; HSPG; heparan sulfate proteoglycan


Biofunctionalization of silicone polymers using poly(amidoamine) dendrimers and a mannose derivative for prolonged interference against pathogen colonization by Analette I. Lopez; Amit Kumar; Megan R. Planas; Yan Li; Thuy V. Nguyen; Chengzhi Cai (pp. 4336-4346).
Despite numerous preventive strategies on bacterial adhesion, pathogenic biofilm formation remained the major cause of medical device-related infections. Bacterial interference is a promising strategy that uses pre-established biofilms of benign bacteria to serve as live, protective coating against pathogen colonization. However, the application of this strategy to silicone urinary catheters was hampered by low adherence of benign bacteria onto silicone materials. In this work, we present a general method for biofunctionalization of silicone (PDMS) as one of the most widely used materials for biomedical devices. We used mild CO2 plasma to activate PDMS surface followed by simple attachment of generation 5 (G5) poly(amidoamine) (PAMAM) dendrimers to generate an amino-terminated surface that were maintained even after storage in PBS buffer for 36 days. We then covalently attach a carboxy-terminated mannose derivative to the modified PDMS to promote the adherence of benign Escherichia coli 83972 expressing mannose-binding type 1 fimbriae. We demonstrated that dense, stable biofilms of E. coli 83972 could be established within 48 h on the mannose-coated PDMS. Significantly, this benign biofilm reduced the adherence of the uropathogenic Enterococcus faecalis by 104-fold after 72 h, while the benign bacteria on the unmodified substrate by only 5.5-fold.

Keywords: Polydimethylsiloxane; Oxidation; Dendrimer; Plasma; Bacterial adhesion; Biofilm


Automated time-resolved analysis of bacteria–substrate interactions using functionalized microparticles and flow cytometry by Xiao Xie; Jens Möller; Rupert Konradi; Malgorzata Kisielow; Alfredo Franco-Obregón; Erich Nyfeler; Andreas Mühlebach; Mamta Chabria; Marcus Textor; Zuhong Lu; Erik Reimhult (pp. 4347-4357).
Surface biofouling poses an increasing problem in industrial and health care applications, driving research for surface coatings to prevent anti-microbial colonization and characterization of the efficacy of the same. The diversity and increasing sophistication of such coatings, which postulate different types of anti-microbial action on planktonic and surface adhering bacteria, challenge the suitability of current approaches to evaluate and compare the different approaches as well as the speed and accuracy at which screening can be made. We describe and provide proof of principle for a method to use microparticles functionalized with molecular coatings through self-assembly together with flow cytometry readout to evaluate Escherichia coli bacteria surface adhesion and killing efficiency. Advantages of the method are the automation of the method that allows recording an immense number of interactions and the possibility to simultaneously record effects on both surface adhering and planktonic bacteria. We demonstrate and discuss design criteria to obtain this information on two coatings, poly( L-lysine)- graft-C3H6N+(CH3)2C12H25 (PLL- g-QAC) and poly( L-lysine)- graft-poly(ethylene glycol)-C3H6N+(CH3)2C12H25 (PLL- g-PEG-QAC), which exemplify two different approaches to creating anti-microbial interfaces. Despite an apparent higher killing efficiency of the PLL- g-QAC during brief exposures, the rapid fouling of that surface quickly reduces its efficiency, whereas the PLL- g-PEG-QAC coating showed greater promise in reducing the growth and interfacial colonization of bacteria over longer time scales.

Keywords: Flow cytometry; Antimicrobial interface; Quaternary ammonium compound; Graft-copolymer; Escherichia coli; Bacteria


Synergistic effects of UV photofunctionalization and micro-nano hybrid topography on the biological properties of titanium by Naoki Tsukimura; Masahiro Yamada; Fuminori Iwasa; Hajime Minamikawa; Wael Att; Takeshi Ueno; Lei Saruwatari; Hideki Aita; Wen-An Chiou; Takahiro Ogawa (pp. 4358-4368).
Titanium surfaces with micro-nano hybrid topography (nanoscale nodules in microscale pits) have been recently demonstrated to show higher biological capability than those with microtopography alone. On the other hand, UV treatment of titanium surfaces, which is called UV photofunctionalization, has recently been introduced to substantially increase the biological capability and osteoconductivity of titanium surfaces. However, synergistic effects of these two advanced surface modification technologies and regulatory factors to potentially modulate the mutual effects have never been addressed. In this study, utilization of a recently discovered controllable self-assembly of TiO2 nanonodules has enabled the exploration of the relative contribution of different sizes of nanostructures to determine the biological capability of titanium surfaces and their relative responsiveness to UV photofunctionalization. Rat bone marrow-derived osteoblasts were cultured on titanium disks with either micropits alone, micropits with 100-nm nodules, micropits with 300-nm nodules, or micropits with 500-nm nodules, with or without UV treatment. Although UV treatment increased the attachment, spread, proliferation, and mineralization of these cells on all titanium surfaces, these effects were more accentuated (3–5 times) on nanonodular surfaces than on surfaces with micropits alone and were disproportionate depending on nanonodule sizes. For instance, on UV-treated micro-nano hybrid surfaces, cell attachment correlated with nanonodule sizes in a quadratic approximation with its peak for 300-nm nodules followed by a decline for 500-nm nodules, while cell attachment exponentially correlated with surface roughness with its plateau achieved for 300-nm nodules without a subsequent decline. Moreover, cell attachment increased in a linear correlation with the surface area, while no significant effect of the inter-irregularities space or degree of hydrophilicity was observed on cell attachment. These results suggest that the effect of UV photofunctionalization can be multiplied on micro-nano hybrid titanium surfaces compared with the surfaces with micropits alone. This multiplication is disproportionately regulated by a selected set of topographical parameters of the titanium surfaces. Among the nanonodules tested in this study, 300-nm nodules seemed to create the most effective morphological environment for responding to UV photofunctionalization. The data provide a systematic platform to effectively optimize nanostructures on titanium surfaces in order to enhance their biological capability as well as their susceptibility to UV photofunctionalization.

Keywords: Implants; Nanotechnology; Osseointegration; Micro-nano hybrid; Nanonodule


Three-dimensional growth of iPS cell-derived smooth muscle cells on nanofibrous scaffolds by Changqing Xie; Jiang Hu; Haiyun Ma; Jifeng Zhang; Lung-Ji Chang; Y. Eugene Chen; Peter X. Ma (pp. 4369-4375).
Induced pluripotent stem cells (iPSCs) have been considered as the major component for personalized regenerative medicine. However, the potential of iPSCs in constructing tissue-engineered (TE) blood vessels has not been exploited. In the present study, we generated mouse iPSCs with the combination of over-expression of 4 iPS factors and knock-down of p53 gene. The established iPSCs were then directed to differentiate into smooth muscle cells (SMCs) with the treatment of 10−5m all-trans retinoid acid (RA). The vehicle dimethyl sulfoxide (DMSO) treatment served as a spontaneous differentiation control. The differentiated cells were then cultured on three-dimensional (3D) macro-porous nanofibrous (NF) poly(l-lactide) (PLLA) scaffolds in vitro. Our data showed that the expression of SMC specific marker genes, including myocardin, smoothelin, SM22α and SMMHC, were higher for the group induced by RA than for the group treated by DMSO, while pluripotent marker gene expression was repressed by the RA-treatment. Upon subcutaneous implantation, the implanted cells maintained the SMC phenotype. In conclusion, the data suggest that iPSCs-derived SMCs can be an important cell source for personalized vascular tissue engineering applications.

Keywords: Induced pluripotent stem cells; Smooth muscle cells; Scaffolds; Vascular tissue engineering


pH-controlled recovery of placenta-derived mesenchymal stem cell sheets by Orane Guillaume-Gentil; Oleg V. Semenov; Andreas H. Zisch; Roland Zimmermann; Janos Vörös; Martin Ehrbar (pp. 4376-4384).
Widely used in different biomedical applications, polyelectrolyte multilayers provide inter alia an attractive way for manufacturing of bio-functionalized, stimuli responsive surface coatings to control cellular behavior. In this study a novel polyelectrolyte-based platform for the engineering and controllable detachment of human mesenchymal stem cell (MSC) sheets is presented. Thin films obtained by layer-by-layer deposition of cationic poly(allylamine hydrochloride) (PAH) and anionic poly(styrene sulfonate) (PSS) polyelectrolytes on conductive indium tin oxide (ITO) electrodes allowed for the fast formation of viable sheets from human placenta-derived mesenchymal stem cells (PD-MSCs). Resulting stem cell sheets retained their phenotypical profile and mesodermal differentiation potency. Both electrochemically-induced local pH lowering and global decrease of the environmental pH allowed for a rapid detachment of intact stem cell sheets. The recovered stem cell sheets remained viable and maintained their capacity to differentiate toward the adipogenic and osteogenic lineages. This novel polyelectrolyte multilayer based platform represents a promising, novel approach for the engineering of human stem cell sheets desired for future clinical applications.

Keywords: Mesenchymal stem cell; Cell sheet; Tissue engineering; Electrochemistry; Polyelectrolyte; Plasticity


Chondrogenesis of adipose stem cells in a porous PLGA scaffold impregnated with plasmid DNA containing SOX trio (SOX-5,-6 and -9) genes by Gun-Il Im; Hye-Joung Kim; Jin H. Lee (pp. 4385-4392).
We developed a chondrogenic scaffold system in which plasmid DNA (pDNA) containing SOX trio ( SOX-5, -6, and -9) genes was incorporated into a PLGA scaffold and slowly released to transfect adipose stem cells (ASCs) seeded in the scaffold. The purpose of this study was to test the in vitro and in vivo efficacy of the system to induce chondrogenic differentiation of ASCs. The pDNA/PEI-PEG complex-incorporated PLGA/Pluronic F127 porous scaffolds were fabricated by a precipitation/particulate leaching method. The following five kinds of pDNA were incorporated into the scaffolds: 1) pECFP-C1 vector without an interposed gene (control group); 2) SOX-5 plasmids; 3) SOX-6 plasmids; 4) SOX-9 plasmids; and 5) one-third doses of each plasmid ( SOX-5, -6, and -9). ASCs were seeded on pDNA-incorporated PLGA scaffolds and cultured in chondrogenic media for 21 days. ASCs were also isolated from rabbits, seeded in pDNA-incorporated PLGA scaffolds, and then implanted in the osteochondral defect created on the patellar groove. The rabbits were sacrificed and analyzed grossly and microscopically 8 weeks after implantation. The percentage of transfected cells was highest on day 14, around 70%. After 21 days, PLGA scaffolds incorporated with each gene showed markedly increased expression of the corresponding gene and protein. Glycosaminoglycan (GAG) assay and Safranin-O staining showed an increased proteoglycan production in SOX trio pDNA-incorporated scaffolds. The COL2A1 gene and protein were notably increased in SOX trio pDNA-incorporated scaffolds than in the control, while COL10A1 protein expression decreased. Gross and histological findings from the in vivo study showed enhanced cartilage regeneration in ASCs/ SOX trio pDNA-incorporated PLGA scaffolds.

Keywords: Adipose stem cell; Chondrogenesis; Gene delivery; SOX trio


The combined bone forming capacity of human periosteal derived cells and calcium phosphates by Scott J. Roberts; Liesbet Geris; Greet Kerckhofs; Eline Desmet; Jan Schrooten; Frank P. Luyten (pp. 4393-4405).
Current knowledge suggests that the periosteum, a fibrous tissue which covers the surface of all bones, contains a population of progenitor cells which mediate the repair of bone defects. In an effort to optimise the utilisation of this source of cells for bone engineering, herein we describe the rational selection of calcium phosphate (CaP) containing materials, based on biomaterial properties, and evaluation of their combined bone forming capacity. Five different commercially available orthopaedic 3D matrices composed of CaP particles in an open collagen network (NuOss™, CopiOs™, Bio-Oss®, Collagraft™ and Vitoss®) were evaluated in vitro and in vivo with human periosteal derived cells (hPDCs). It was found that the cell–material combinations behaved quite differently in vivo, despite apparent in vitro similarities in gene expression profiles. Bone formation was highest within the NuOss™/hPDC implant at 13.03%, which also contained the highest incidence of bone marrow formation. The bone formed in this implant was chimeric with approximately 65% originating from implanted cells. Upon analysis of human specific gene expression, although it was found that predominantly osteogenic differentiation was observed within NuOss™/hPDC implants, a lesser induction of chondrogenic genes was also observed. The formation of a cartilage intermediate was confirmed by histology. Additionally the NuOss™/hPDC implant integrated into the mouse environment with apparent active scaffold resorption. This study demonstrates the importance of matching a cell support/biological matrix with a cell type and subsequently has outlined parameters which can be used for the rational selection of biomaterials for bone engineering.

Keywords: Progenitor cell; Bone regeneration; Osteogenesis; Calcium phosphate; Scaffold


Modulation of fibrin matrix properties via knob:hole affinity interactions using peptide–PEG conjugates by Allyson S.C. Soon; Christine S. Lee; Thomas H. Barker (pp. 4406-4414).
Fibrin is a widely used biological scaffold in tissue engineering and regenerative medicine. While the polymerization dynamics from its soluble precursor fibrinogen has been studied for decades, few attempts have been made to modulate fibrin network structure through the addition of external agents that actively engage this process. We propose the use of polyethylene glycol (PEG)-based linkers that interact with fibrinogen via knob:hole affinity interactions as a means of controlling thrombin-mediated fibrin polymerization dynamics and resulting network structure. Using bivalent and tetravalent knob-PEG conjugates with sizes ranging from 2 to 20 kDa, we demonstrate that the clotting characteristics of fibrinogen solutions can be altered in a dose-dependent manner, with conjugate size playing a major role in altering fibrin network structure. Interestingly, factor XIIIa-catalyzed fibrin(ogen) crosslinking and plasmin-mediated degradation were not significantly impacted. This work demonstrates the feasibility of modulating fibrin network structure through the addition of knob-PEG conjugates that perturb the polymerization process through non-covalent knob:hole interactions.

Keywords: Fibrin; Fibrinogen; Polyethylene oxide; Hydrogel


Therapeutic lymphangiogenesis using stem cell and VEGF-C hydrogel by Ji Hye Hwang; In Gul Kim; Ji Young Lee; Shuyu Piao; David S. Lee; Tae Seung Lee; Jeong Chan Ra; Ji Youl Lee (pp. 4415-4423).
Lymphedema is a manifestation of lymphatic system insufficiency. It arises from primary lymphatic dysplasia or secondary obliteration after lymph node dissection or irradiation. Although improvement of swelling can be achieved by comprehensive non-operative therapy, treatment of this condition requires lifelong care and good compliance. Recently molecular-based treatments using VEGF-C have been investigated by several researchers. We designed the present study to determine whether the therapeutic efficacy of implanted human adipose-derived stem cells (hADSCs) could be improved by applying a gelatin hydrogel containing VEGF-C (VEGF-C hydrogel) to the site of tissue injury in a lymphedema mouse model. Four weeks after the operation, we evaluated edema and determined lymphatic vessel density at various post-operative time points. Mice treated with hADSCs and VEGF-C hydrogel showed a significantly decreased dermal edema depth compared to the groups of mice that received hADSCs only or VEGF-C hydrogel only. Immunohistochemical analysis also revealed that the hADSC/VEGF-C hydrogel group showed significantly greater lymphatic vessel regeneration than all the other groups. hADSCs were detected in the implantation sites of all mice in the hADSC/VEGF-C group, and exhibited a lymphatic endothelial differentiation phenotype as determined by co-staining PKH-labeled hADSCs for the lymphatic marker LYVE-1. Our results suggest that co-administration of hADSCs and VEGF-C hydrogel has a substantial positive effect on lymphangiogenesis.

Keywords: Lymphangiogenesis; Stem cell; Hydrogel; VEGF-C


The impact of compositional topography of amniotic membrane scaffold on tissue morphogenesis of salivary gland by Ya-Chuan Hsiao; Hao-Wei Lee; You-Tzung Chen; Tai-Horng Young; Tsung-Lin Yang (pp. 4424-4432).
Amniotic membrane (AM) has been widely used in the reconstruction of oral epithelial defects. However, whether it is also effective in facilitating tissue formation of salivary gland, an appendix of oral epithelia, has never been explored. To investigate the effects and the underlying mechanism of AM on salivary gland morphogenesis, murine fetal submandibular gland (SMG) explants were cultured on different preparations of AM scaffolds. It was found that, on AM stromal scaffold, SMG demonstrated well-developed branching morphogenesis. Nonetheless, on AM epithelial scaffold, SMG epithelial cell converted to a spindle-shape, lost intercellular connection, changed cytoskeletal organization, and exhibited scattering behaviors. Meanwhile, the integrity of SMG basement membrane was dismantled as well. However, when acellular AM epithelial scaffold was used, cultured SMG demonstrated organized morphology, indicating that AM epithelial component provided specific surface features for SMG morphogenesis. To further investigate AM scaffold morphogenetic effect, it was found hepatocyte growth factor (HGF), an epithelial scattering factor, was expressed abundantly in cultivated AM epithelia. After blocking HGF function of AM, cultured SMG regained branching activity, reorganized cell adhesion and subcellular organization, and reproduced basement membranes. Therefore, AM-derived bioactive factor profoundly influences cell behaviors and structure formation of SMG. Together, this study showed that compositional topography of AM scaffold is important in affecting SMG morphogenesis. By understanding the effects of AM scaffold on SMG morphogenesis, it provides important information for rationally designing and fabricating AM scaffold for salivary gland regeneration.

Keywords: Salivary gland; Amniotic membrane; Morphogenesis; Branching


Development of bioengineered human larynx by Silvia Baiguera; Alessandro Gonfiotti; Massimo Jaus; Camilla E. Comin; Milena Paglierani; Costantino Del Gaudio; Alessandra Bianco; Domenico Ribatti; Paolo Macchiarini (pp. 4433-4442).
To date, only two human laryngeal allotransplants have been reported and, although they were successful, both patients required life-long immunosuppression. A bioengineered human larynx could represent a possible alternative to allotransplantation. Human larynxes were decellularized enzymatically to obtain acellular matrices. Histological and molecular analysis demonstrated that all cellular components and nuclear material were removed. SEM showed that decellularized matrices retained the hierarchical structures of the native larynx, and mechanical tests demonstrated that the decellularization did not significantly impaired the biomechanically properties of the obtained matrices. Immunohistochemical staining found residual angiogenic factors after decellularization, and CAM analysis demonstrated that acellular laryngeal scaffolds induce a strong in vivo angiogenic response. Using a decellularization method, we are now able to obtain, in a short and clinically useful time, natural bioengineered laryngeal scaffolds which could be use for partial or total implantation in humans.

Keywords: Human larynx; Acellular matrix; Decellularization protocol; Mechanical properties; Morphological properties; Angiogenesis


pH-responsive polymers for trehalose loading and desiccation protection of human red blood cells by Andrew L. Lynch; Rongjun Chen; Nigel K.H. Slater (pp. 4443-4449).
PP-50, a synthetic pH-responsive biopolymer, is here shown to increase the permeability of the phospholipid bilayer to trehalose, a disaccharide accumulated in desiccation tolerant organisms across all kingdoms. Uptake of 251 ± 6 mm intracellular trehalose facilitated an increase in the membrane integrity of vacuum dried cells by a factor of 9 ± 1 and reduced extent of hemoglobin oxidation in dried cells from 66 ± 1% to 23 ± 3%. To elucidate the mechanism of PP-50 mediated trehalose delivery, permeability studies were conducted using molecules ranging in size from sucrose to 10 kDa poly(ethylene glycol). It was shown that the logarithm of relative diffusant membrane permeability decreased linearly with diffusant molecular volume, suggesting transport via non-Stokesian diffusion. Consistent with this conclusion, topographic atomic force micrographs reported membrane thinning proximate to PP-50 adsorption on the erythrocyte membrane, a phenomenon associated with increased incidence of phospholipid hydrocarbon chain bending.

Keywords: Biopolymer; Blood; Cryopreservation; Trehalose; Cell viability


Enhanced anti-tumor activity and safety profile of targeted nano-scaled HPMA copolymer-alendronate-TNP-470 conjugate in the treatment of bone malignances by Ehud Segal; Huaizhong Pan; Liat Benayoun; Pavla Kopečková; Yuval Shaked; Jindřich Kopeček; Ronit Satchi-Fainaro (pp. 4450-4463).
Bone neoplasms, such as osteosarcoma, exhibit a propensity for systemic metastases resulting in adverse clinical outcome. Traditional treatment consisting of aggressive chemotherapy combined with surgical resection, has been the mainstay of these malignances. Therefore, bone-targeted non-toxic therapies are required. We previously conjugated the aminobisphosphonate alendronate (ALN), and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer. HPMA copolymer-ALN-TNP-470 conjugate exhibited improved anti-angiogenic and anti-tumor activity compared with the combination of free ALN and TNP-470 when evaluated in a xenogeneic model of human osteosarcoma. The immune system has major effect on toxicology studies and on tumor progression. Therefore, in this manuscript we examined the safety and efficacy profiles of the conjugate using murine osteosarcoma syngeneic model. Toxicity and efficacy evaluation revealed superior anti-tumor activity and decreased organ-related toxicities of the conjugate compared with the combination of free ALN plus TNP-470. Finally, comparative anti-angiogenic activity and specificity studies, using surrogate biomarkers of circulating endothelial cells (CEC), highlighted the advantage of the conjugate over the free agents. The therapeutic platform described here may have clinical translational relevance for the treatment of bone-related angiogenesis-dependent malignances.

Keywords: Polymer therapeutics; HPMA copolymer; TNP-470; Alendronate; Osteosarcoma


Spatiotemporal effects of a controlled-release anti-inflammatory drug on the cellular dynamics of host response by Tram T. Dang; Kaitlin M. Bratlie; Said R. Bogatyrev; Xiao Y. Chen; Robert Langer; Daniel G. Anderson (pp. 4464-4470).
In general, biomaterials induce a non-specific host response when implanted in the body. This reaction has the potential to interfere with the function of the implanted materials. One method for controlling the host response is through local, controlled-release of anti-inflammatory agents. Herein, we investigate the spatial and temporal effects of an anti-inflammatory drug on the cellular dynamics of the innate immune response to subcutaneously implanted poly(lactic-co-glycolic) microparticles. Noninvasive fluorescence imaging was used to investigate the influence of dexamethasone drug loading and release kinetics on the local and systemic inhibition of inflammatory cellular activities. Temporal monitoring of host response showed that inhibition of inflammatory proteases in the early phase was correlated with decreased cellular infiltration in the later phase of the foreign body response. We believe that using controlled-release anti-inflammatory platforms to modulate early cellular dynamics will be useful in reducing the foreign body response to implanted biomaterials and medical devices.

Keywords: Foreign body response; Controlled drug release; Dexamethasone; Cellular dynamics; Inflammatory proteases


The role of adenosine receptor and caveolae-mediated endocytosis in oligonucleotide-mediated gene transfer by Yi-Chen Chung; Ting-Yun Cheng; Tai-Horng Young (pp. 4471-4480).
We previously reported the preparation and characterization of ternary nanoparticles with the negative surface charge, which comprises histidine-conjugated polyallylamine (PAA-HIS)/DNA core complex and a single-stranded oligonucleotide outer layer, to transfect various cell lines. As a continued effort, here the investigations on the endocytotic mechanisms involved in the uptake of the oligonucleotide-coated PAA-HIS/DNA complexes are reported. Interestingly, these complexes showed enhanced transfection efficiency only when deoxyadenosine-containing oligonucleotides were deposited on the PAA-HIS/DNA complex surface. The addition of uncomplexed oligonucleotide, free adenosine and adenosine receptor antagonist significantly inhibited the transfection efficiency of oligonucleotide-coated PAA-HIS/DNA complexes. These results indicated that the oligonucleotide-coated PAA-HIS/DNA complexes could specifically recognize adenosine receptors on the cell surface and were taken up by adenosine receptor-mediated process. Uptake and transfection experiments with various endocytic inhibitors suggested that, after receptor/ligand binding, oligonucleotide-coated PAA-HIS/DNA/complexes were mainly internalized via caveolae-mediated pathway to result in effective intracellular processing for gene expression. In conclusion, both adenosine receptor and caveolae-mediated endocytosis play important roles in oligonucleotide-mediated gene transfer.

Keywords: Oligonucleotide; Gene delivery; Adenosine; Endocytosis; Caveolae

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