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Biomaterials (v.28, #33)

Editorial board (pp. ifc).

Stress–corrosion crack growth of Si–Na–K–Mg–Ca–P–O bioactive glasses in simulated human physiological environment by Don R. Bloyer; James M. McNaney; Rowland M. Cannon; Eduardo Saiz; Antoni P. Tomsia; Robert O. Ritchie (pp. 4901-4911).
This paper describes research on the stress–corrosion crack growth (SCCG) behavior of a new series of bioactive glasses designed to fabricate coatings on Ti and Co–Cr-based implant alloys. These glasses should provide improved implant fixation between implant and exhibit good mechanical stability in vivo. It is then important to develop an understanding of the mechanisms that control environmentally assisted crack growth in this new family of glasses and its effect on their reliability. Several compositions have been tested in both static and cyclic loading in simulated body fluid. These show only small dependences of SCCG behavior on the composition. Traditional SCCG mechanisms for silicate glasses appear to be operative for the new bioactive glasses studied here. At higher velocities, hydrodynamic effects reduce growth rates under conditions that would rarely pertain for small natural flaws in devices.

Keywords: Stress corrosion; Bioactive glass; Subcritical crack growth; Fatigue; Fracture


Connexin 43 expression of foreign body giant cells after implantation of nanoparticulate hydroxyapatite by Katja Herde; Sonja Hartmann; Ralph Brehm; Olaf Kilian; Christian Heiss; Anne Hild; Volker Alt; Martin Bergmann; Reinhard Schnettler; Sabine Wenisch (pp. 4912-4921).
In bone a role of connexin 43 has been implicated with the fusion of mononuclear precursors of the monocyte/macrophage lineage into multinucleated cells. In order to investigate the putative role of connexin 43 in formation of bone osteoclast-like foreign body giant cells which are formed in response to implantation of biomaterials, nanoparticulate hydroxyapatite had been implanted into defects of minipig femura. After 20 days the defect areas were harvested and connexin 43 expression and synthesis were investigated by using immunohistochemistry, Western Blot, and in situ hybridization within macrophages and osteoclast-like foreign body giant cells. Morphological analysis of gap junctions is performed ultrastructurally. As shown on protein and mRNA level numerous connexin 43 positive macrophages and foreign body giant cells (FBGC) were localized within the granulation tissue and along the surfaces of the implanted hydroxyapatite (HA). Besides, the formation of FBGC by fusion of macrophages could be shown ultrastructurally. Connexin 43 labeling observed on the protein and mRNA level could be attributed to gap junctions identified ultrastructurally between macrophages, between FBGC, and between FBGC and macrophages. Annular gap junctions in the cytoplasm of FBGC pointed to degradation of the channels, and the ubiquination that had occurred in the course of degradation was confirmed by Western blot analysis. All in all, the presently observed pattern of connexin 43 labeling refers to an functional role of gap junctional communication in the formation of osteoclast-like foreign body giant cells formed in response to implantation of the nanoparticulate HA.

Keywords: Bone; Connexin 43; Foreign body giant cells; Fusion; Hydroxyapatite


A 12 month in vivo study on the response of bone to a hydroxyapatite–polymethylmethacrylate cranioplasty composite by Hiroshi Itokawa; T. Hiraide; M. Moriya; M. Fujimoto; G. Nagashima; R. Suzuki; T. Fujimoto (pp. 4922-4927).
We investigated the osteoconductivity and biocompatibility in vivo of a new hydroxyapatite–polymethylmethacrylate (HA–PMMA) composite developed for use as an implant material for cranioplasty, which is expected to have the good osteoconductivity of HA together with the strength and ease of handling of PMMA. The HA–PMMA composites were implanted in eight full-grown beagles and then 6, 12, 24 weeks and 1 year after implantation, the animals were sacrificed and the implanted materials removed along with the surrounding tissues. Extirpated specimens were studied using an optical microscope and micro-computed tomography (micro-CT). Fibrous connective tissue was prominent in the interface of the composite at 6 weeks. New bone formation was seen around the implant, 12 and 24 weeks after operation. At 1 year, new bone filled in the interface of the HA–PMMA composite and adhered to the surrounding autogenous bone. Mixing HA and PMMA did not interfere with the osteoconductivity of the HA component. In micro-CT findings, the new bone growing on the HA–PMMA composite could be seen attaching preferentially to HA particles exposed at the composite surface, rather than the PMMA. This study demonstrated that this HA–PMMA composite is a good candidate for cranial bone implants due to its good osteoconductivity and biocompatibility.

Keywords: Hydroxyapatite–polymethylmethacrylate composite; Osteoconductivity; Biocompatibility; Cranioplasty; In vivo


The effect of hyaluronic acid incorporation on fibroblast spreading and proliferation within PEG-diacrylate based semi-interpenetrating networks by Jaishankar K. Kutty; Eunhee Cho; Jeoung Soo Lee; Naren R. Vyavahare; Ken Webb (pp. 4928-4938).
The nanometer-scale mesh size of many synthetic crosslinked hydrogel networks restricts encapsulated cells to a rounded morphology that can inhibit cellular processes such as proliferation and migration that are essential for the early stages of remodeling and tissue formation. The objective of these studies was to investigate an approach for accelerating cellular remodeling based on the creation of semi-interpenetrating networks (IPNs) composed of hydrolytically degradable poly(ethylene glycol) (PEG) diacrylate macromers and native, enzymatically degradable extracellular matrix (ECM) components (collagen, gelatin and hyaluronic acid (HA)). Among the three ECM components investigated, addition of HA at concentrations of 0.12% w/v and greater supported fibroblast spreading throughout the three-dimensional network and significantly increased proliferation relative to control hydrogels without HA. Incorporation of HA resulted in relatively small changes in hydrogel physical/chemical properties such as swelling, degradation rate, and elastic modulus. Fibroblast spreading was eliminated by the addition of hyaluronidase inhibitors, demonstrating that cell-mediated enzymatic degradation of HA is a necessary mechanism responsible for the observed increases in fibroblast activity. By accelerating early cellular remodeling and growth, these semi-IPNs may be useful vehicles for cell transplantation in a variety of tissue engineering applications.

Keywords: Hydrogel; Hyaluronic acid; Cell spreading; Cell proliferation; Fibroblast


Cellular control of tissue architectures using a three-dimensional tissue fabrication technique by Yukiko Tsuda; Tatsuya Shimizu; Masayuki Yamato; Akihiko Kikuchi; Tadashi Sasagawa; Sachiko Sekiya; Jun Kobayashi; Guoping Chen; Teruo Okano (pp. 4939-4946).
Tissue engineering seeks to provide regenerated tissue architectures in vitro but has not yet successfully created thick, highly vascularized, multi-functional tissues replicating native structure. We describe a novel method to fabricate pre-vascularized tissue equivalents using multi-layered cultures combining micro-patterned endothelial cells as vascular pre-cursors with fibroblast monolayer sheets as tissue matrix. Stratified tissue equivalents are constructed by alternately layering fibroblast monolayer sheets with patterned endothelial cell sheets harvested from newly developed thermo-responsive micro-patterned surfaces alternating 20μm-wide cell-adhesive lanes with 60μm non-adhesive zones. Cell culture substrates covalently grafted with different thermo-responsive polymers permit spatial switching of cell adhesion and detachment using applied small temperature changes. Endothelial cell patterning fidelity was maintained within the multi-layer tissue constructs after assembly, leading to self-organization into microvascular-like networks after 5-day tissue culture. This novel technique holds promise for the study of cell-cell communications and angiogenesis in reconstructed, three-dimensional environments as well as for the fabrication of tissues with complex, multicellular architecture.

Keywords: Thermally responsive material; Endothelial cell; Co-culture; Micropatterning; 3-D fabrication; Tissue engineering


Active targeting of brain tumors using nanocarriers by Beduneau Arnaud Béduneau; Patrick Saulnier; J.-P. Jean-Pierre Benoit (pp. 4947-4967).
The delivery of drugs to brain tumors is limited by the presence of the blood–brain barrier (BBB) separating the blood from the cerebral parenchyma. An understanding of the specific mechanisms of the brain capillary endothelium has led to the development of various strategies to enhance the penetration of drugs into the brain tissue. Active targeting is a non-invasive approach, which consists in transporting drugs to target organs using site-specific ligands. Drug-loaded nanocarriers capable of recognizing brain capillary endothelial cells and cerebral tumoral cells have shown promising potential in oncology. Endogenous and chimeric ligands binding to carriers or receptors of the BBB have been directly or indirectly conjugated to nanocarriers. This review indexes the main targeted colloidal systems used for drug delivery to the brain. Their pharmacological behavior and their therapeutic effect are discussed.

Keywords: Nanocarriers; Active targeting; Brain tumors; Endogenous ligands; Monoclonal antibodies; Receptor-mediated transcytosisAbbreviations; 5-FU; 5-fluorouracil; ABC; ATP-binding cassette; AME; adsorptive-mediated endocytosis; APO; apolipoproteins; BBB; blood–brain barrier; BCEC; brain capillary endothelial cells; BSA; bovin serum albumin; CAT1; cationic amino acids transporter 1; CBSA; cationized bovin serum albumin; CMC; critical micelle concentration; CMT; carrier-mediated transport; CNS; central nervous system; CSF; cerebrospinal fluid; DNA; deoxyribonucleic acid; DMPC; 1; 2-dipalmitoyl-; sn; -glycero-3-phosphatidylcholine; DPPE; dipalmitoylphosphatidylethanolamine; DSPE; distearoylphosphatidylethanolamine; DTT; dithiotreitol; EAAT; excitatory amino acid transporter; EGFR; epidermal growth factor receptor; FA folic acid; FBP; folate-binding protein; FR; folate receptor; GLUT1; glucose transporter 1; IGF; insulin-like growth factor; IL; interleukin; LAT1; large neutral amino-acid transporter 1; LDC; lipid–drug conjugates; LDL; low-density lipoproteins; LNC; lipid nanocapsules; LUV; large unilamellar vesicle; MAb; monoclonal antibodies; MBS; N; -maleimidobenzoyl-; N; -hydroxysuccinimide; MCT1; monocarboxylic acid transporter 1; MLV; multilamellar vesicle; MNP; model nanoparticles; MRNA; messenger ribonucleic acid; MRT; mean residence time; MTFA; 5′-methyltetrahydrofolic acid; NHS; N; -hydroxysuccinimide; NLC; nanostructured lipid carriers; OCT; organic cations transporter; PAsp; poly(aspartic acid); PACA; poly(alkylcyanoacrylate); PCL; poly(; ε; -caprolactone); PCPP-SA; poly(carboxypropane)-sebacic acid; PDNA; plasmid deoxyribonucleic acid; PE; phosphatidylethanolamine; PEG; polyethylene glycol; PGlu; poly(glutamic acid); PHDCA; poly(hexadecylcyanoacrylate); p; I; isoelectric point; PIBCA; poly(isobuty2-cyanoacrylate); PIT; phase-inversion temperature; PLA; poly(lactic acid); RES; reticuloendothelial system; RME; receptor-mediated endocytosis; RMT; receptor-mediated transcytosis; SA; streptavidin; SATA; N; -succinimidyl-2-mercapto-[; S; -acetyl]acetic acid; SLN; solid lipid nanoparticles; SPDP; N; -succinimidyl-3(2-pyridyldithio)propionate; SUV; small unilamellar vesicle; TE; toxoplasmic encephalitis; Tf; transferrin; TfR; transferrin receptor


The mechanical properties of the skin epidermis in relation to targeted gene and drug delivery by Mark A.F. Kendall; Yu-Foong Chong; Alexander Cock (pp. 4968-4977).
A challenge in combating many major diseases is breaching the skin's tough outer layer (the stratum corneum (SC)) and delivering drugs and genes into the underlying abundant immunologically sensitive viable epidermal cells with safe, practical physical technologies. To achieve this effectively and accurately, design information is needed on key skin mechanical properties when pushing into and through epidermal skin cells. We measure these important mechanical properties by penetrating through the intact SC and viable epidermis (VE) of freshly excised murine skin with a NANO-indenter, using custom tungsten probes fabricated with nominally 5 and 2μm diameters (with nanoscale tips). We show the skin Young's modulus, storage modulus and stress all dramatically decreased through the SC. Also, for a given penetration depth, decreasing the probe size significantly increases the storage modulus. Biological variation in penetrating the skin was shown. These collective findings advance the rational design of physical approaches for delivering genes and drugs within key cells of the VE.

Keywords: Dermis; Drug delivery; Mechanical properties; NANO-indenter; Vaccines


Design of targeted lipid nanocapsules by conjugation of whole antibodies and antibody Fab’ fragments by Beduneau Arnaud Béduneau; Patrick Saulnier; F. Hindre François Hindré; Anne Clavreul; Jean-Christophe Leroux; Jean-Pierre Benoit (pp. 4978-4990).
Immunonanocapsules were synthesized by conjugation to lipid nanocapsules (LNC) of whole OX26 monoclonal antibodies (OX26 MAb) directed against the transferrin receptor (TfR). The TfR is overexpressed on the cerebral endothelium and mediates the transcytosis mechanism. Fab’ fragments, known for their reduced interaction with the reticuloendothelial system, were also conjugated to LNC. This coupling was facilitated by the incorporation of lipid PEG2000 functionalized with reactive-sulfhydryl maleimide groups (DSPE–PEG2000–maleimide) into LNC shells by a post-insertion procedure, developed initially for liposome pegylation. An interfacial model using the dynamic rising drop technique helped determine the parameters influencing the DSPE–PEG2000–maleimide insertion and the quality of the anchorage. Heat was essential to promote both an important and stable adsorption of DSPE–PEG2000–maleimide onto LNC. OX26 MAb were thiolated to react with maleimide functions whereas thiol residues on Fab’ fragments were used directly. The number of ligands per nanocapsule was adjusted according to their initial quantity in the coupling reaction mixture, with densities from 16 to183 whole antibodies and between 42 and 173 Fab’ fragments per LNC. The specific association of immunonanocapsules to cells overexpressing TfR was thus demonstrated, suggesting their ability to deliver drugs to the brain.

Keywords: Immunonanocapsules; Ox26 monoclonal antibody; Fab’ fragment; Transferrin receptor; Brain targeting; Interfacial rheology


Targeted binding of PLA microparticles with lipid-PEG-tethered ligands by Wynter J. Duncanson; Michael A. Figa; Kevin Hallock; Samuel Zalipsky; James A. Hamilton; Joyce Y. Wong (pp. 4991-4999).
Solid core polymeric particles are an attractive delivery vehicle as they can efficiently encapsulate drugs of different physical and chemical characteristics. However, the effective targeting of such particles for therapeutic purposes has been somewhat elusive. Here, we report novel polymeric particles comprised of poly(lactic acid) (PLA) with incorporated poly(ethylene glycol)-lipids (PEG-lipids). Particles are characterized for morphology, surface charge, and composition with field-emission scanning electron microscopy (FESEM), zeta potential measurements, and proton nuclear magnetic resonance (1H NMR) spectroscopy, respectively. The surface densities of PEG lipids determined by1H NMR and particle size distributions are consistent with scaling theory for adsorption of chains onto a surface. We observe significant binding of liganded PEG-lipid tethers when the molecular weight is greater than the unliganded PEG-lipids for significant binding events. Importantly, the binding is not completely lost when the unliganded PEG molecular weight is greater than the liganded PEG-lipid tether. We observe a similar trend for the lower affinity ligand (thioctic acid), but the degree of binding is significantly lower than the high affinity ligand (biotin). This novel technique used to fabricate these liganded particles combined with the lipid bilayer binding studies provides a platform for systematic optimization of particle binding.

Keywords: Drug delivery; Microsphere; Surface modification; Poly(lactic acid); Lipid


Systematic study of osteoblast response to nanotopography by means of nanoparticle-density gradients by Tobias P. Kunzler; Christoph Huwiler; Tanja Drobek; Voros Janos Vörös; Nicholas D. Spencer (pp. 5000-5006).
Features over a wide range of length scales affect the biological response to a surface. While the influence of micro-features has been extensively studied, the effect of nano-features has only rarely been systematically investigated. We have developed a simple method to produce nano-featured gradients by kinetically controlled adsorption of negatively charged silica nanoparticles onto positively charged, poly(ethylene imine) (PEI)-coated silicon wafers. Subsequent sintering of the particles allowed a tuning of the particle morphology and resulted in a firm anchoring of the particles to the surface. Particle-density gradients were characterized by atomic force microscopy (AFM). Cell experiments with rat calvarial osteoblasts (RCO) on nano-featured gradients exhibited a significant decrease in proliferation at locations with higher particle coverage. Seven days post seeding, the number of osteoblasts was eight times higher at positions without particles compared to positions with maximum particle coverage. While cells spread well and developed a well-organized actin network in the absence of particles, spreading and formation of a strong actin network was considerably hindered at locations with maximum particle density.

Keywords: Cell proliferation; Cell morphology; Nanotopography; Nanoparticle; Osteoblast

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