Abstract: New tissue engineering technologies will rely on biomaterials that physically support tissue growth and stimulate specific cell functions. The goal of this study was to create a biomaterial that combines inherent biological properties which can specifically trigger desired cellular responses (e.g., angiogenesis) with electrical properties which have been shown to improve the regeneration of several tissues including bone and nerve. To this end, composites of the biologically active polysaccharide hyaluronic acid (HA) and the electrically conducting polymer polypyrrole (PP) were synthesized and characterized. Electrical conductivity of the composite biomaterial (PP/HA) was measured by a four-point probe technique, scanning electron microscopy was used to characterize surface topography, X-ray photoelectron spectroscopy and reflectance infrared spectroscopy were used to evaluate surface and bulk chemistry, and an assay with biotinylated hyaluronic acid binding protein was used to determine surface HA content. PP/HA materials were also evaluated for in vitro cell compatibility and tissue response in rats. Smooth, conductive, HA-containing PP films were produced; these films retained HA on their surfaces for several days in vitro and promoted vascularization in vivo. PP/HA composite biomaterials are promising candidates for tissue engineering and wound-healing applications that may benefit from both electrical stimulation and enhanced vascularization.

Abstract: This paper reviews the present status of studies of biocompatibility of diamond-like carbon (DLC) and carbon nitride (CN) coatings. DLC and CN coatings, due to their novel mechanical and tribological properties, chemical inertness, electrical and optical properties, and biocompatibility, are excellent candidates for biomedical applications. A number of clinical applications for DLC are now being considered by commercial manufacturers of surgical implants. Preliminary studies have shown that DLC coating can be adherent on a range of biomaterials with desirable bulk properties, no toxicity toward living cells, no inflammatory response or loss of cell integrity, as well no cellular damage. Despite only a few reports about biocompatibility of CN coating, which, with its mechanical and chemical properties comparable with DLC, is a very attraction coating material for future biomedical applications. This paper outlines the present level of research and suggests areas for future research, these include in vivo tests and a more detailed investigation of coating bond structure or properties.

Abstract: Strategies to engineer bone have focused on the use of natural or synthetic degradable materials as scaffolds for cell transplantation or as substrates to guide bone regeneration. The basic requirements of the scaffold material are biocompatibility, degradability, mechanical integrity, and osteoconductivity. A major design problem is satisfying each of these requirements with a single scaffold material. This study addresses this problem by describing an approach to combine the biocompatibility and degradability of a polymer scaffold with the osteoconductivity and mechanical reinforcement of a bonelike mineral film. We report the nucleation and growth of a continuous carbonated apatite mineral on the interior pore surfaces of a porous, degradable polymer scaffold via a one step, room temperature incubation process. A 3-dimensional, porous scaffold of the copolymer 85:15 poly(lactide-co-glycolide) was fabricated by a solvent casting, particulate leaching process. Fourier transform IR spectroscopy and scanning electron microscopy (SEM) analysis after different incubation times in a simulated body fluid (SBF) demonstrate the growth of a continuous bonelike apatite layer within the pores of the polymer scaffold. Quantification of phosphate on the scaffold displays the growth and development of the mineral film over time with an incorporation of 0.43 mg of phosphate (equivalent to 0.76 mg of hydroxyapatite) per scaffold after 14 days in SBF. The compressive moduli of polymer scaffolds increased fivefold with formation of a mineral film after a 16-day incubation time as compared to control scaffolds. In summary, this biomimetic treatment provides a simple, one step, room temperature method for surface functionalization and subsequent mineral nucleation and growth on biodegradable polymer scaffolds for tissue engineering.

Abstract: Melt derived 45S5 Bioglass(R) has been studied for more than 25 years. Bioglass(R) has excellent biocompatibility, and its surface reactivity has contributed to its clinical success over the past 10 years. Recently, porous bioactive glasses have been derived through sol-gel processing in an attempt to increase the specific surface area, and, thus, the surface reactivity and degradability of the material. This allows the material to be replaced ultimately by natural tissue while it stimulates bone regeneration. In this work, the processing and properties of these sol-gel bioactive glasses are discussed, and a new drying method and treatment is described to make homogeneous particulate and monoliths on a production scale.

Abstract: Controlled drug delivery is gaining importance over the conventional methods of drug administration because of its inherent benefits. Self-regulated release from the delivery vehicle may enhance drug potency with a sustained action. The present study describes a novel hydrogel blend of polyacrylamide with chitosan for controlled delivery of antibiotics. Hydrogel was synthesized by cross-linking acrylamide-chitosan mixture (8:2 v/v) with N,N' methylene bisacrylamide. Hydrogel was characterized for surface morphology, hydrophilicity, pH-dependent swelling properties, cytotoxicity, and control release properties. Scanning electron microscopy (SEM) revealed the macroporous surface morphology of the matrix with average pore size at 104 +/- 7.61 mu. Hydrogel was found to be highly hydrophilic as assessed by octane contact angle (154.5 + 0.572) measurement. Hydrogel showed no cytotoxic effects on NIH3T3 and HeLa cells up to 40% of extract concentrations as determined by MTT and neutral red assay. This showed hydrogel biocompatibility and thus absence of deleterious effects of the hydrogel on cell viability and functionality. Hydrogels did not show any pH-dependent swelling profile, and they swelled considerably to achieve a swelling ratio of approximately 16.0 at the end of 24 hr. Amoxicillin was incorporated in the hydrogel matrix as a candidate antibiotic for release studies. In vitro release studies of amoxicillin revealed the sustained nature of delivery and matrix released 56.47 + 1.12% and 77.096 + 1.72% of amoxicillin at the end of 24 and 75 hr, respectively. Although in vivo studies are awaited, the present study provides enough documentation to consider polyacrylamide-chiotsan hydrogel as a possible candidate for controlled delivery of antibiotics.

Abstract: The true aim of biomaterials research is to create implant surfaces which interact actively with the biological system and provoke exactly the same reactions as the corporal tissues do. The improvement in the interface compatibility of polymers selected for implantation by directed surface modification is an important contribution to biomaterial development. Different polymer properties are adjusted and characterized independently of the carrier polymer by means of introduction of modern surface analytical methods and surface techniques. In addition, the interactions between the modified polymer surface and the biological system are measured. In this way, the hydrophilization of a polyurethane (Tecoflex™) and a poly(ether sulfone) by plasma induced graftcopolymerization of hydrogels like poly (hydroxyethyl methacrylate) leads to improved blood compatibility. Functionalization by means of SO2 plasma treatment of medical grade poly(vinyl chloride) increases the adsorption of the basal membrane protein fibronectin, which correlates with an improvement in cell growth. A suitable interface for an improved cell growth of human vascular endothelial cells as well as for cornea endothelial cells has been created by immobilization of the cell adhesion mediator fibronectin using bifunctional spacer molecules at several carrier polymer surfaces like smooth poly(vinyl chloride), modified polyurethane, Tecoflex™ and poly (dimethyl siloxane).

Abstract: Conformational changes of proteins adsorbing on biomaterial surfaces affect biocompatibility. Titanium is among the most successful biomaterials; however, the mechanisms leading to its biocompatibility are not yet understood. The primary objective of this study was to investigate the conformation of human plasma fibrinogen (HPF) adsorbed on titanium oxide surfaces. A method for preparing ultraflat titanium substrates was developed. This allowed high-resolution investigation of both the titanium oxide surfaces and the adsorbed state of HPF. The titanium oxide surfaces were first imaged with an atomic force microscope in air and subsequently incubated in a solution of HPF in phosphate buffer and imaged in fluid with tapping mode AFM. The titanium oxide surfaces exhibited a root-mean-squared (RMS) roughness of (0.29 ± 0.03) nm over (1.00 × 1.00) μm2 areas. Different degrees of molecular order were found on the titanium oxide surface. In crystalline surface areas square lattices with parameters a0 = b0 ≈ 0.5 ...

Abstract: An implantable medical device comprising a drug-loaded polymer overlaid with a fabric that promotes tissue ingrowth is useful in a wide variety of tissue engineering applications. The invention includes, for example, prosthetic heart valves, annuloplasty rings, and grafts, having enhanced biocompatibility and biostability. Methods of making and using the implantable medical devices of the invention are also included.

Abstract: The biocompatibility of ethylene-vinyl acetate copolymer (EVAc), polyethylene (PE), and polyaniline (PANi) films in the emeraldine (EM), nigraniline (NA) and leucoemeraldine (LM) intrinsic oxidation states were assessed through subcutaneous implantation into male Sprague-Dawley rats beneath the dorsal skin, for a period ranging from 19 to 90 weeks Histological examination, interstitial pressure measurement, and X-ray photoelectron spectroscopy (XPS) were employed to determine the biocompatibility of the polymers The polymers did not provoke inflammatory responses in the subcutaneous tissues over the entire implantation period Characteristics features associated with tissue-implant incompatibility were not evident near the implantation Interstitial pressure was measured to evaluate the development of tissue Low interstitial pressure readings on the region of implantation confirmed the biocompatibility of these polymer types The surface composition of the electroactive aniline polymers before and after the implantation was characterized by XPS

Abstract: Chitin and chitosan (a deacetylated derivative of chitin) have been proposed for biomedical applications because of their biocompatibility and abundance in nature. We have investigated the effect of the percentage of deacetylation (%DD) of chitosan on biocompatibility from two sources, shrimp and cuttle fish, with two cell lines, L929 and BHK21(C13). The difference in %DD for each source was approximately 10% in the range of 76–90%. Biocompatibility was investigated for: (1) cell adherence and growth on the chitosan samples as substrate; (2) the effect of extract media on 2d and 7d growth; and (3) the presence of an inhibition zone. The results were similar for both cell lines. The chitosan samples were air-dried on to tissue culture-grade petri dishes to provide a substrate for the adherent-cell cultures. The higher %DD substrates from each source supported attachment of the cells, while the lower %DD did not. Cells cultured in medium conditioned by each substrate (i.e. extract medium) displayed an initial difference in growth which was abrogated in cultures incubated for 7 days. No inhibition zone was apparent. However, after 7 days, some cells were noted migrating on to the low %DD substrate disks. The morphology of these cells was changed with the presence of pseudopodia being apparent. Thus, especially with regard to attachment the %DD has a very important effect on the biocompatibility of the chitosan and should be monitored carefully.

Abstract: A novel hydrogel, CHITOXAN(TM) (CH-X), has potential as a vehicle for controlled drug delivery. The hydrogel is obtained by complexation of two polysaccharides, chitosan and xanthan. In the present work we investigated the biocompatibility of the complex using in vitro and in vivo models. The cytotoxic effects of CH-X microspheres as well as their degradation products at different concentrations were assessed on fibroblasts (fibroblast cell line L-929) using 3-(4,5-dimethylthiazole-2yl)-2,5-triphenyl tetrazolium) (MTT). The test is based on mitochondrial dehydrogenase cell activity as an indicator of cell viability. Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) cytokines as well as nitric oxide (NO) production by macrophages (macrophage cell line J-774) were examined as indicators of cell activation. In vivo biocompatibility assessment was performed for 1 to 12 weeks. This study was performed using tablets obtained after compression of CH-X particles implanted at the subcutaneous level in male Wistar rats. CH-X biocompatibility and degradation were investigated using histological studies. Light and transmission electron microscopy (TEM) analyses were used to determine the foreign-body reaction and phagocytosis of the implants by macrophages. Fibroblast exposition to CH-X particles and degradation products did not show cytotoxic effects as measured by MTT test. TNF-alpha production was dependent on CH-X particles concentration, whereas IL-1beta production was found to be dose independent. CH-X extract products stimulated TNF-alpha secretion when used at the highest concentration (10 mg/mL), notably after 28 days' degradation time. No effect was observed on IL-1beta production when CH-X extracts were used in comparison to the control. The effects of CH-X particles on NO secretion were similar as on TNF-alpha. Histological studies showed that CH-X tablets broke down into particles which progressively degraded into smaller fragments. A significant fraction of the fragments was ingested by the macrophages after 12 weeks of implantation. Light microscopy studies showed a weak foreign-body reaction as a function of time and the fibrous layer thickness decreased with time of implantation.

Abstract: Failures of small internal diameter vascular grafts have been caused by the lack of a stable endothelial lining to form on their artificial surfaces. Polymer surfaces can be optimized by means of proper treatment to allow a homogeneous and uniform coverage in artificial prosthesis applications. Several solutions were studied to improve cell attachment and growth on artificial materials. In the present study, polyethyleneterephthalate (PET) surfaces were treated by plasma processes with oxygen and ammonia and also in the presence of a gas mixture to verify the effect of functional groups grafting onto the endothelial cell growth. Related surface chemical modifications were investigated by X-ray photoelectron spectroscopy (XPS). Then using cytotoxicity and cytocompatibility tests, the biocompatibility of the modified PET surfaces was assessed by studying the behavior of human umbilical vein endothelial cells (HUVEC). The results showed that plasma-treated PET samples have no toxic effect on HUVEC. The cytocompatibility tests revealed an increase in cell growth with incubation time and the presence of well-spread and flattened cells (SEM analyses). Thus it is reported that plasma treatments can improve PET biocompatibility to HUVEC.

Abstract: A novel approach described earlier for improving polymer substratum biocompatibility(1) is further elucidated. Polysulfone (PSf) spin-coating films were modified by covalent end-on grafting of hydrophilic and sterically demanding photo-reactive poly(ethylene glycol) (PEG) conjugates (ABMPEG; 10 kDa). The degree of grafting density was varied systematically, yielding a wide spectrum of attained surface characteristics monitored by air-water contact angles (captive bubble method). Fibronectin (FN) adsorption was studied by in situ ellipsometry and found to decrease monotonically as ABMPEG grafting density increased. The adhesive interaction of human skin fibroblasts with these substrata and, in particular, the effect of FN precoating were investigated in detail. A clear optimum of cell-substratum interactions was found for mildly modified substrata, employing well established microscopic and immunofluorescence techniques, namely the monitoring of cell adhesion and spreading, overall cell morphology, organization of FN receptors, and focal adhesions as well as FN matrix formation. The results suggest that cell interactions with hydrophobic polymer substrata are enhanced considerably when modified with hydrophilic and sterically demanding PEG moieties at a low surface coverage due to enhanced biologic activity of adsorbed and intercalated adhesive proteins such as FN.

Abstract: This review links together recent information on the biocompatibility of Nitinol. Fundamental aspects of biological responses to Nitinol and its alloy components are clarified. The clinical advantages of using this functional biomaterial are evident. Although most studies support the good biocompatibility of Nitinol, there are still a lot of unanswered questions. The long-term in vivo performance of this material has not been well demonstrated, and host-Nitinol interactions at cell and molecular level are mostly unknown. However, the experimental and clinical data strongly support Nitinol as a safe biomaterial, at least as good as stainless steel or titanium alloys.

Abstract: ZrO2/Al2O3 composites were prepared by mixing a tetragonal ZrO2, stabilized by 5.31 mol% Y2O3 and 4.45 mol% Nb2O5, and various amounts of Al2O3. Influence of the amount of Al2O3 on strength and toughness and tetragonal phase stability in the composites under autoclave conditions was investigated. In addition, in vitro and in vivo biocompatibility of the composites was examined. The composite, prepared with addition of 20 vol% Al2O3, exhibited the highest strength of 700 MPa and toughness of 8.1 MPa · m1/2 and showed no hydrothermal degradation while aging in an autoclave. The biocompatibility of the composite exhibited no cytotoxicity and no significant adverse soft-tissue response for up to 3 months implant period in guinea pigs. © 2000 John Wiley & Sons, Inc. J Biomed Mater Res (Appl Biomater) 53: 438–443, 2000

Abstract: The aim of this study was to test C/C material (carbonized, graphitized or covered with pyrolytic carbon) designated for the use in orthopaedic and bone surgery Using an in vitro assay we confirmed, that the cell proliferation was exhibited the mostly on the C/C composite coated with pyrolitic carbon and afterwards polished The two latest of subsequent water extracts of this material had a slightly inhibiting effect on the cells metabolic activity Biocompatibility test in vivo performed subcutaneously on rats did not show big differences between three tested implants (C/C composite, epoxy resine, titanium alloy), on the other hand the plates tested on pigs demonstrated foreign-body reaction induced by wear C/C composite material Such debris were found both in the neighborhood of the implant as well as in the lymphatic node

Abstract: Membranes made from 4 commercial poly(carbonate urethanes): Carbothane (CB), Chronoflex (CF), Corethane 80A (CT80), and Corethane 55D (CT55), and from 2 poly(ether urethanes): Tecoflex (TF) and Tecothane (TT) were prepared by solution casting and sterilized by either ethylene oxide (EO) or gamma radiation. Their biocompatibility was evaluated in vitro in terms of proliferation, cell viability, and adhesion characteristics of human umbilical veins (HUVEC), monocytes (THP-1), and skin fibroblasts, and by measuring complement activation through the generation of the C3a complex. Their hemocompatibility was determined by measuring the level of radiolabeled platelet, neutrophil, and fibrin adhesion in an ex vivo arteriovenous circuit study in piglets as well as via an in vitro hemolysis test. The results of this study showed no endothelial cell proliferation on any of the materials. The cell viability study revealed that the CB, CF, and TF membranes sterilized by EO maintained the highest percentage of monocyte viability after 72 h of incubation (>70%) while none of the gamma-sterilized membranes displayed any cell viability. The fibroblast adhesion and C3a generation assays revealed that none of the materials supported any cell adhesion or activated complement, regardless of the sterilization method. The hemolysis test also confirmed that the 4 poly(carbonate urethanes) were hemolytic while none of the poly(ether urethanes) were. Finally, the ex vivo study revealed that significantly more platelets adhered to the CB and CT55 membranes while the levels of neutrophil and fibrin deposition were observed to be similar for all 6 materials. In conclusion, the study identified the CF and TF membranes as having superior biocompatibility and hemocompatibility compared to the other polyurethanes.

Abstract: The biocompatibility of a viscous, hydrophobic, bioerodible poly(ortho ester) (POE) intended for intraocular application was investigated. POE was evaluated as a blank carrier and as containing modulators of degradation. Each formulation was injected intracamerally and intravitreally in rabbit eyes, and clinical and histological examinations were performed postoperatively for 2 weeks. In the case of intracameral injections, polymer biocompatibility appeared to depend on the amount injected in the anterior chamber. When 50 microL was administered, the polymer degraded within 2 weeks, and clinical observations showed good biocompatibility of POE with no toxicity to the ocular tissues or increase in intraocular pressure. The injection of a larger volume, 100 microL, of POE, appeared inappropriate because of direct contact of polymeric material with the corneal endothelium, and triggered reversible edema and inflammation in the anterior chamber of the eye that regressed after a few days. After intravitreal administration, POE was well tolerated and no inflammatory reaction developed during the observation period. The polymer degraded slowly, appearing as a round whitish bubble in the vitreous cavity. The presence of modulators of degradation both improved POE biocompatibility and prolonged polymer lifetime in the eye. POE appears to be a promising biomaterial for clinical intraocular application.

Abstract: The coatings of hydroxyapatite are widely used for orthopaedic and dental prostheses. Nevertheless, their chemical, biological and mechanical properties still can be improved by the development of new preparation technologies. Here we report a surface characterization of hydroxyapatite coatings prepared by different deposition techniques. The layers of hydroxyapatite are grown on commercial titanium substrates by using sol-gel and electrodeposition techniques. The biocompatibility of the samples is tested upon in vitro treatment as a function of the exposure time. Surface chemical composition and morphology of the coatings are studied by means of x-ray photoelectron spectroscopy (XPS), scanning Auger microscopy (SAM) and scanning electron microscopy (SEM). Quantitative XPS analysis and surface chemical and physical images reveal different features (cleanness, homogeneity, roughness) of the coatings and different surface modifications induced by the interaction with osteoblast cells.

Abstract: Biocomposite layers of silica and various bone-relevant proteins such as collagen, gelatine and commercial collagen hydrolysate can be obtained from coatings of silica sols mixed with proteins in water/dioxane. Investigations into the mechanical and cell proliferation properties for different sol parameters (pH, solvent), type and concentration of proteins, annealing and crosslinking of the biocomposite layers revealed that such coatings are highly biocompatible with excellent mechanical properties.

Abstract: Although graphitic carbon has been known and used as a biomaterial for a very long time, the excellent biocompatibility of diamond-like carbon (DLC) films has been addressed only in a few cases. We anticipate the combination of bioinert DLC films and surface-immobilized bioactive biomolecules with antithrombogenic properties, such as the polysaccharide heparin, as a straightforward concept to optimize the haemocompatibility of a wide variety of materials. Therefore, to assess this property in view of an application as vascular grafts, surface analytical studies on DLC-coated and heparinized polymer and silicon substrates were performed. The DLC films were deposited on polytetrafluoroethylene (PTFE), PTFE vascular prostheses, polystyrene and silicon wafers by an energetic acetylene plasma beam and subsequently exposed to an ammonia plasma before heparin was covalently coupled to such functionalized surfaces by an end-point attachment method. The biochemical characterization by thrombin tests revealed, in accordance with XPS measurements, a high amount of heparin on the surface and an extended blood coagulation time. Thus, the efficiency of the plasma treatment for functionalization and successful improvement of the haemocompatibility of DLC films could be shown.