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Cochlear implant fixation using titanium screws
Lee, D. J. and M. Driver (2005), Laryngoscope 115(5): 910-1.

Co-effect of aqueous solubility of drugs and glycolide monomer on in vitro release rates from poly(D,L-lactide-co-glycolide) discs and polymer degradation
Kim, J. M., K. S. Seo, et al. (2005), J Biomater Sci Polym Ed 16(8): 991-1007.
Abstract: The objective of this study was to investigate the effect of aqueous solubility of model drugs and glycolide monomer (GM) from poly(D,L-lactide-co-glycolide) (PLGA) discs on in vitro release rates and polymer degradation. 5-Fluorouracil (5-FU), a water-soluble compound, and dexamethasone in a water-insoluble base form were selected as model drugs. Glycolide monomer, that has moderate solubility in water, was a non-toxic and biodegradable additive as a derivative material of hydrolysis of PLGA in order to obtain desirable drugs release rates. PLGA discs with or without GM were formulated by means of compression molding method. The prepared polymeric discs were incubated at 37 degrees C in phosphate-buffered saline (PBS, pH 7.4) and characterized at scheduled time points for water uptake, mass loss, diameter and morphology change, molecular weight and composition change using scanning electron microscopy (SEM), gel-permeation chromatography (GPC), and H-NMR, respectively. The supernatants were taken out of the sample vials and were analyzed for drug release. The 5-FU release was found to be increasing in proportion to the drug loading amount with an initial burst for 5 days, while dexamethasone release showed inverse relationship with the increasing drug loading amount. However, the release behaviors of 5-FU and dexamethasone polymeric discs containing GM showed faster release rates than control discs (without GM) and did not show lag periods during the in vitro release test due to adding GM, which acted as a channeling agent that has moderate solubility in water. Polymer degradation was found to be affected by aqueous solubility of drugs and GM. In conclusion, we observed that drugs release rates were influenced by their aqueous solubility and loading amount and also GM plays a major role in controlling drug release rates regardless of solubility of drugs. This system appears to be promising for controlled drug delivery aimed at local therapy.

Collagen as a biomaterial
Stenzel, K. H., T. Miyata, et al. (1974), Annu Rev Biophys Bioeng 3(0): 231-53.

Collagen based biomaterials: an ideal way of increasing their resistance to infection
Gunasekaran, S. and M. Chvapil (1988), Biomater Artif Cells Artif Organs 16(4): 771-83.
Abstract: Collagen and gelatin containing biomaterials are relatively more susceptible to bacterial infection. Systemic administration or local delivery of antibiotics after implantation does not seem to solve the problem either effectively or easily. Antibiotics may be incorporated in the implant; but many, being water soluble, are quickly absorbed and not effective for adequate time periods. Resorcinol monoacetate (RMA) is a relatively water insoluble antibacterial agent which partially crosslinks collagen and has the potential to be an intrinsic antibiotic in collagenous bioprostheses. This study confirms the efficacy of RMA as a chemical that: (a) mildly crosslinks collagen at pH 3.5-4.5; (b) releases very slowly from the pretreated collagen sponge when washed in aqueous medium; (c) inhibits bacterial growth on the pretreated collagen sponges, at 2% (w/w) concentration, for at least 12 days; (d) remains biocompatible under treated conditions.

Collagen engineering for biomaterial use
Miyata, T., T. Taira, et al. (1992), Clin Mater 9(3-4): 139-48.
Abstract: Collagen is a typical biological macromolecule having been utilized for a long period of time as a material like cellulose. However, its application is becoming comprehensive, ranging from classical applications such as the leather, gelatine and food industries to the current one, namely, biomaterial and biotechnological uses. The diversification of collagen applications was enhanced by two factors, the accumulation of the scientific knowledge that permitted proper engineering of collagen for a biomaterial use, and the demand for new biomaterials with characteristic biological properties including interaction with cells. The collagen engineering described in this paper is designed for biomaterial use, based on the fundamental chemical and biological properties of collagen; however, it would be useful also for other applications apart from biomaterials.

Collagen fiber orientation in human peri-implant bone around immediately loaded and unloaded titanium dental implants
Traini, T., M. Degidi, et al. (2005), J Periodontol 76(1): 83-9.
Abstract: BACKGROUND: The main factor in determining the mechanical properties of bone is the collagen configuration. METHODS: This study investigated the birefringence in human bone around loaded and unloaded titanium dental implants to evaluate the collagen fiber orientation using circularly polarized light (CPL) and scanning electron microscopy (SEM). A total of 10 titanium dental implants, five immediately loaded and five unloaded, were used. The birefringence measurements were performed on digitized images of both loaded and unloaded implants. All images detected at 50x were measured using a software image analysis. RESULTS: In the bone around loaded implants, the transverse collagen fiber area was 45,481+/-3,037 pixel2 (mean+/-SD), while the area of longitudinal collagen fibers was 13,676+/-2,232 pixel2 (mean+/-SD). In the unloaded implants, the transverse collagen fiber area was 32,174+/-2,554 pixel2 (mean+/-SD), while the area of longitudinal collagen fibers was 89,073+/-1,960 pixel2 (mean+/-SD). The CPL measurements of the birefringence for transverse collagen fibers of loaded versus unloaded implants indicated that the differences were statistically significant (P <0.05). The results for the longitudinal collagen fibers of loaded versus unloaded implants were also statistically significant (P <0.05). CONCLUSIONS: In the bone around loaded dental implants, transverse collagen fibers were more abundant, while in the unloaded implants, collagen fibers run more longitudinally. The load seemed to determine the collagen fiber orientation.

Collagen-based biomaterials
Ramshaw, J. A., J. A. Werkmeister, et al. (1996), Biotechnol Genet Eng Rev 13: 335-82.

Collagen-based biomaterials
Werkmeister, J. A. and J. A. Ramshaw (1992), Clin Mater 9(3-4): 137-8.

Collagen-based biomaterials as 3D scaffold for cell cultures: applications for tissue engineering and gene therapy
Chevallay, B. and D. Herbage (2000), Med Biol Eng Comput 38(2): 211-8.
Abstract: Many substances are used in the production of biomaterials: metals (titanium), ceramics (alumina), synthetic polymers (polyurethanes, silicones, polyglycolic acid (PGA), polylactic acid (PLA), copolymers of lactic and glycolic acids (PLGA), polyanhydrides, polyorthoesters) and natural polymers (chitosan, glycosaminoglycans, collagen). With the rapid development in tissue engineering, these different biomaterials have been used as three-dimensional scaffolds and cell transplant devices. The principal biochemical and biological characteristics of the collagen-based biomaterials are presented, including their interactions with cells (fibroblasts), distinct from those of synthetic polymers, and their potential use in gene therapy through the formation of neo-organs or organoids.

Collagen--biomaterial for drug delivery
Friess, W. (1998), Eur J Pharm Biopharm 45(2): 113-36.
Abstract: The use of collagen as a biomaterial is currently undergoing a renaissance in the tissue engineering field. The biotechnological applications focus on the aspects of cellular growth or delivery of proteins capable of stimulating cellular response. However, basic knowledge about collagen biochemistry and the processing technology in combination with understanding of the physico-chemical properties is necessary for an adequate application of collagen for carrier systems. The purpose of this review article is to summarize information available on collagen dosage forms for drug delivery as well as to impart an overview of the chemical structures and the galenical properties including detailed description of the processing steps - extraction, purification, chemical crosslinking and sterilization. The most successful and stimulating applications are shields in ophthalmology, injectable dispersions for local tumor treatment, sponges carrying antibiotics and minipellets loaded with protein drugs. However, the scientific information about manipulating release properties or mechanistic studies is not as abundant as for some synthetic polymers.

Collagen-carbon nanotube composite materials as scaffolds in tissue engineering
MacDonald, R. A., B. F. Laurenzi, et al. (2005), J Biomed Mater Res A 74(3): 489-96.
Abstract: Carbon nanotubes (CNT) are attractive for use in fiber-reinforced composite materials due to their very high aspect ratio, combined with outstanding mechanical and electrical properties. Composite materials comprising a collagen matrix with embedded CNT were prepared by mixing solubilized Type I collagen with solutions of carboxylated single-walled carbon nanotubes (SWNT) at concentrations of 0, 0.2, 0.4, 0.8, and 2.0 weight percent. Living smooth muscle cells were incorporated at the time of collagen gelation to produce cell-seeded collagen-CNT composite matrices. Constructs containing 2.0 wt % CNT exhibited delayed gel compaction, relative to lower concentrations that compacted at the same rate as pure collagen controls. Cell viability in all constructs was consistently above 85% at both Day 3 and Day 7, whereas cell number in CNT-containing constructs was lower than in control constructs at Day 3, though statistically unchanged by Day 7. Scanning electron microscopy showed physical interactions between CNT and collagen matrix. Raman spectroscopy confirmed the presence of CNT at the expected diameter (0.85-1.30 nm), but did not indicate strong molecular interactions between the collagen and CNT components. Such collagen-CNT composite matrices may have utility as scaffolds in tissue engineering, or as components of biosensors or other medical devices.

Collagen-coated polylactide microspheres as chondrocyte microcarriers
Hong, Y., C. Gao, et al. (2005), Biomaterials 26(32): 6305-13.
Abstract: Polylactide (PLA) microspheres were coated with collagen for cell culture and injectable cell carriers. Utilizing a method of emulsion-solvent evaporation, PLA microspheres with diameter ranging from 180 to 280 microm were prepared, followed with aminolysis in hexanediamine/n-propanol solution to introduce free amino groups on their surfaces. After the amino groups were transferred into aldehyde groups by a treatment of glutaraldehyde, collagen type I was covalently coupled via Schiff base formation between the aldehyde groups and the amino groups on collagen molecules. Meanwhile, physically entangled collagen molecules were retained following a grafting-coating protocol to yield microspheres coated with larger amount of collagen. Aminolysis resulted in weight loss of the microspheres following a linear relationship with the aminolysis time. The NH2 and collagen contents existed on the microsphere surface were quantitatively determined by ninhydrin and hydroproline (Hyp) analyses, respectively. Larger amount of collagen was immobilized on the microspheres with higher content of NH2. In vitro chondrocyte culture revealed that the cells could attach, proliferate and spread on these PLA microspheres, in particular on the ones having higher content of collagen. These results show that the collagen-coated PLA microspheres are promising candidate as cell microcarriers.

Colloid surface chemistry critically affects multiple particle tracking measurements of biomaterials
Valentine, M. T., Z. E. Perlman, et al. (2004), Biophys J 86(6): 4004-14.
Abstract: Characterization of the properties of complex biomaterials using microrheological techniques has the promise of providing fundamental insights into their biomechanical functions; however, precise interpretations of such measurements are hindered by inadequate characterization of the interactions between tracers and the networks they probe. We here show that colloid surface chemistry can profoundly affect multiple particle tracking measurements of networks of fibrin, entangled F-actin solutions, and networks of cross-linked F-actin. We present a simple protocol to render the surface of colloidal probe particles protein-resistant by grafting short amine-terminated methoxy-poly(ethylene glycol) to the surface of carboxylated microspheres. We demonstrate that these poly(ethylene glycol)-coated tracers adsorb significantly less protein than particles coated with bovine serum albumin or unmodified probe particles. We establish that varying particle surface chemistry selectively tunes the sensitivity of the particles to different physical properties of their microenvironments. Specifically, particles that are weakly bound to a heterogeneous network are sensitive to changes in network stiffness, whereas protein-resistant tracers measure changes in the viscosity of the fluid and in the network microstructure. We demonstrate experimentally that two-particle microrheology analysis significantly reduces differences arising from tracer surface chemistry, indicating that modifications of network properties near the particle do not introduce large-scale heterogeneities. Our results establish that controlling colloid-protein interactions is crucial to the successful application of multiple particle tracking techniques to reconstituted protein networks, cytoplasm, and cells.

Colloidal beta-tricalcium phosphate prepared by discharge in a modified body fluid facilitates synthesis of collagen composites
Shibata, Y., H. Yamamoto, et al. (2005), J Dent Res 84(9): 827-31.
Abstract: The development of hydroxyapatite/collagen composites that are naturally synthesized and need no additional treatment is required for use in bone repair. Since reducing the diameter can increase the specific surface area of calcium phosphate particles that can conjugate collagen molecules, we expected colloidal calcium phosphates of submicron diameter obtained by discharge to be effective in formulating these composites. Additionally, since biodegradable beta-tricalcium phosphate has better osteoconductivity than hydroxyapatite, this study aimed to investigate the synthesis of colloidal hydroxyapatite and beta-tricalcium phosphate/collagen composites. Collagen molecules were tightly polymerized in the beta-tricalcium phosphate/collagen composite by catalysis of the generated -P-O-P- polyphosphate chain. Bonding strength between collagen NH+ amino groups and -P-O-P-, and cross-linking of the Ca++-RCOO- in the collagen were increased compared with those in the hydroxyapatite/collagen composite. These chemical reactions due to colloidal beta-tricalcium phosphate might play a key role in the synthesis of collagen composites.

Colon targeted delivery systems: review of polysaccharides for encapsulation and delivery
Kosaraju, S. L. (2005), Crit Rev Food Sci Nutr 45(4): 251-8.
Abstract: Colon-targeted delivery of bioactives has recently gained importance in addressing specific needs in the therapy of colon-based diseases. Many approaches have been attempted for the development of colon-specific delivery systems, with not much success in the past. Recent research into the utilization of the metabolic activity and the colonic microenvironment in the lower gastrointestinal tract has attained great value in the design of novel colon-targeted delivery systems based on natural biodegradable polymers. In the current article, special emphasis has been placed on polysaccharide systems, with minimal chemical modification, that have been exploitedfor colon targeting. These polysaccharide based encapsulation and targeted delivery systems are envisaged to have an immense potential for the development of food/nutraceutical formulations for colon-based diseases, including colorectal cancer.

Combination of vascularized outer-table calvarial bone graft based on the superficial temporal vessels and allomatrix for the repair of an orbito-frontal blow-out fracture in a child
Ali, F., A. S. Halim, et al. (2005), J Craniomaxillofac Surg 33(5): 326-30.
Abstract: CASE PRESENTATION: A vascularized outer-table calvarial bone graft was used for repairing a Posnick type 2 traumatic orbito-frontal bone defect supported by the use of a calcium-based putty (Allomatrix) in a 7-year-old girl. Gaps between the donor and recipient sites were filled with Allomatrix containing demineralized bone matrix particles. Four years later there was a good cosmetic result using an artificial left eye. DISCUSSION: Orbito-frontal defects have been repaired using iso-, allo- or xenografts as well as synthetic materials. Anatomical studies have pointed to the importance of the superficial temporal vessels for the vascular supply of a graft to the calvaria. CONCLUSION: The vascularized outer-table calvarial bone graft based on the superficial temporal vessels is a reliable option for repairing bony defects in the craniofacial skeleton especially in irradiated or scarred areas where there is a paucity of well-vascularized tissues. It also has the potential for bony growth in children.

Combinatorial evaluation of the host-guest chemistry of star-shaped block copolymers
Meier, M. A. and U. S. Schubert (2005), J Comb Chem 7(3): 356-9.

Combinatorial screening of cell proliferation on poly(L-lactic acid)/poly(D,L-lactic acid) blends
Simon, C. G., Jr., N. Eidelman, et al. (2005), Biomaterials 26(34): 6906-15.
Abstract: We have combined automated fluorescence microscopy with a combinatorial approach for creating polymer blend gradients to yield a rapid screening method for characterizing cell proliferation on polymer blends. A gradient in polymer blend composition of poly(L-lactic acid) (PLLA) and poly(D,L-lactic acid) (PDLLA) was created in the form of a strip-shaped film and was annealed to allow PLLA to crystallize. Fourier transform infrared (FTIR) microspectroscopy was used to determine the composition in the gradients and atomic force microscopy was used to characterize surface topography. Osteoblasts were cultured on the gradients and proliferation was assessed by automated counting of cells using fluorescence microscopy. Surface roughness varied with composition, was smooth on PDLLA-rich regions and was rough on the PLLA-rich regions. Cell adhesion was similar on all regions of the gradients while proliferation was faster on the smooth, PDLLA-rich end of the gradients than on the rough, PLLA-rich end of the gradients. These results demonstrate the feasibility of a new, combinatorial approach for evaluating cell proliferation on polymer blends.

Combined angiogenic and osteogenic factor delivery enhances bone marrow stromal cell-driven bone regeneration
Huang, Y. C., D. Kaigler, et al. (2005), J Bone Miner Res 20(5): 848-57.
Abstract: Bone formation is a coordinated process involving various biological factors. We have developed a scaffold system capable of sustained and localized presentation of osteogenic (BMP-4) and angiogenic (VEGF) growth factors and human bone marrow stromal cells to promote bone formation at an ectopic site. Combined delivery of these factors significantly enhanced bone formation compared with other conditions. INTRODUCTION: Tissue regeneration entails complex interactions between multiple signals and materials platforms. Orchestrating the presentation of these signals may greatly enhance the regeneration of lost tissue mass. Bone formation, for example, is dependent on the signaling of BMPs, molecules initiating vascularization (e.g., vascular endothelial growth factor [VEGF]), and osteogenic precursor cells capable of responding to these cues and forming bone tissue. It was hypothesized that combined and concerted delivery of these factors from biodegradable scaffolds would lead to enhanced bone formation. MATERIALS AND METHODS: Poly(lactic-co-glycolic acid) scaffolds containing combinations of condensed plasmid DNA encoding for BMP-4, VEGF, and human bone marrow stromal cells (hBMSCs) were implanted into the subcutaneous tissue of SCID mice. Implants (n = 6) were retrieved at 3, 8, and 15 weeks after implantation. Bone and blood vessel formation was determined qualitatively and quantitatively by methods including histology, immmunostaining, and muCT. RESULTS: Scaffolds delivering VEGF resulted in a prominent increase in blood vessel formation relative to the conditions without VEGF. BMP-4 expression in scaffolds encapsulating condensed DNA was also confirmed at the 15-week time-point, showing the characteristic of long-term delivery in this system. Combined delivery of all three types of factors resulted in a significant increase in the quantity of regenerated bone compared with any factor alone or any two factors combined, as measured with DXA, X-ray, and histomorphometric analysis. Furthermore, bone formed with all three factors had elastic moduli significantly higher than any other condition. CONCLUSIONS: Concerted delivery of BMP-4, VEGF, and hBMSCs promoted greater bone formation relative to any single factor or combination of two factors. Materials systems that allows multifactorial presentation more closely mimic natural developmental processes, and these results may have important implications for bone regeneration therapeutics.

Combined DNA vaccine encapsulated in microspheres enhanced protection efficacy against Mycobacterium tuberculosis infection of mice
Cai, H., X. D. Hu, et al. (2005), Vaccine 23(32): 4167-74.
Abstract: In a study to develop novel vaccination strategies against tuberculosis, we encapsulated DNA encoding Ag85B, MPT-64 and MPT-83 antigens mixed with dimethyldioctyldecyl ammonium bromide (DDA) into biodegradable poly(dl-lactide-co-glycolide, PLGA) microspheres. Scanning electron microscopy (SEM) analysis demonstrated a uniform microsphere population with a mean diameter of <5microm. Using RT-PCR we were able to demonstrate antigen gene expression in selected tissue. Moreover, in mice injected with PLGA encapsulated DNA, the levels of expression appeared to be higher comparing to those injected with non-encapsulated DNA. Also, C57BL/6 mice immunized with a single dose of PLGA encapsulated DNA produced increased levels of IFN-gamma in the supernatant of spleen cells when cultured in the presence of the recombinant antigens. High levels of specific IgG antibody against the three antigens were also observed. In vaccine/challenge experiments, mice receiving a single dose of PLGA encapsulated DNA were protected against Mycobacterium tuberculosis challenge at levels comparable to groups of mice immunized with three doses of non-encapsulated DNA vaccine or with Mycobacterium bovis BCG.

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