Fabrication Of Medical Devices Research Articles

Poly(vinyl alcohol)–acrylamide hydrogels as load-bearing cartilage substitute

Poly(vinyl alcohol) (PVA) has been advanced as a biomaterial for the fabrication of medical devices to be used as synthetic articular cartilage because of its viscoelastic nature, high water content, and biocompatibility. Key material requirements for such devices are high creep resistance to prevent mechanical instability in the joint and high water content to maintain a lubricious surface to minimize wear and damage of the cartilage counterface during articulation. The creep resistance of PVA hydrogels can be increased by high temperature annealing; however this process also collapses the pores, reducing the water content and consequently reducing the lubricity of the hydrogel surface [Bodugoz-Senturk H, Choi J, Oral E, Kung JH, Macias CE, Braithwaite G, et al. The effect of polyethylene glycol on the stability of pores in polyvinyl alcohol hydrogels during annealing. Biomaterials 2008;29(2):141–9.]. We hypothesized that polymerizing acrylamide (AAm) in the pores of the PVA hydrogel would minimize the loss of lubricity during annealing by preventing the collapse of the pores and loss of water content. Increasing AAm content increased porosity and equilibrium water content and decreased the coefficient of friction, tear strength, crystallinity, and creep resistance in annealed PVA hydrogels.

Nanostructured Titanium for Biomedical Applications

Metallic materials, for example, stainless steel, titanium and its alloys, and tantalum, are widely used for medical implants in trauma surgery, orthopedic and oral medicine. Successful incorporation of these materials for design, fabrication and application of medical devices require that they meet several critical criteria. Paramount is their biocompatibility as expressed by their relative reactivity with human tissues. Another is their ability to provide sufficient mechanical strength, especially under cyclic loading conditions to ensure the durability of the medical devices made therefrom. Finally the material should be machinable and formable thereby enabling device fabrication at an affordable cost. In this paper we show that nanostructured commercial purity titanium produced by severe plastic deformation (SPD) opens new avenues and concepts for medical implants, providing benefits in all areas of medical device technology. Numerous clinical studies of medical devices fabricated from commercial purity (CP) titanium for trauma, orthopaedic and oral medicine has proven its excellent biocompatibility. However the mechanical strength of CP titanium is relatively low compared to other metals used in biomedical devices. Whereas the strength of this material can be increased by either alloying or secondary processing, for example rolling, drawing, etc., these enhancements normally come with some degradation in biometric response and fatigue behaviour. Recently it has been shown that nanostructuring of CP titanium by SPD processing can provide a new and promising alternative method for improving the mechanical properties of this material. This approach also has the benefit of enhancing the biological response of the CP titanium surface. This paper reports the results of the first developments and studies of nanostructured titanium (n-Ti), produced as long-sized rods with superior mechanical and biomedical properties and demonstrates its applicability for dental implants. The effort was conducted using commercially pure Grade 4 titanium [C – 0.052 %, O2 – 0.34 %, Fe – 0.3 %, N – 0.015 %, Ti-bal. (wt. pct.)]. Nanostructuring involved SPD processing by equal-channel angular pressing followed by thermo-mechanical treatment (TMT) using forging and drawing to produce 7 mm diameter bars with a 3 m length. This processing resulted in a large reduction in grain size, from the 25 lm equiaxed grain structure of the initial titanium rods to 150 nm after combined SPD and TMT processing, as shown in Figure 1. The selected area electron diffraction pattern, Figure 1(c), further suggests that the ultra fine grains contained predominantly high-angle non-equilibrium grain boundaries with increased grain-to-grain internal stresses. A similar structure for CP Ti can be produced in small discs using other SPD methods, for example – high pressure torsion (HPT) as studied in detail. In the present work it was essential to produce homogeneous ultrafine-grained structure throughout a three-meter length rod to enable the pilot production of implants and provide sufficient material for thorough testing of the mechanical and bio-medical properties of the nanostructured titanium. Table 1 illustrates mechanical property benefits attainable by nanostructuring of CP titanium, for example, the strength of the nanostructured titanium is nearly twice that of conventional CP titanium. Notably this improvement has been achieved without the drastic ductility reductions (to below C O M M U N IC A IO N S

Interfacing biomembrane mimetic polymer surfaces with living cells – Surface modification for reliable bioartificial liver

The surface design used for reducing nonspecific biofouling is one of the most important issues for the fabrication of medical devices. We present here a newly synthesized a carbohydrate-immobilized phosphorylcholine polymer for surface modification of medical devices to control the interface with living cells. A random copolymer composed of 2-methacryloyloxyethyl phosphorylcholine (MPC), n-butyl methacrylate (BMA), and 2-lactobionamidoethyl methacrylate (LAMA) was synthesized by conventional radical polymerization. The monomer feeding ratio in the copolymer was adjusted to 24/75/1 (MPC/BMA/LAMA). The copolymer (PMBL1.0) could be coated by solvent evaporation from an ethanol solution. Cells of the human hepatocellular liver carcinoma cell line (HepG2) having asialoglycoprotein receptors (ASGPRs) were seeded on PMBL1.0 or poly(BMA) (PBMA)-coated PET plates. On PBMA, many adherent cells were observed and were well spread with monolayer adhesion. HepG2 adhesion was observed on PMBL1.0 because the cell has ASGPRs. Furthermore, some of the cells adhering to PMBL1.0 had a spheroid formation and similarly shaped spheroids were scattered on the surface. According to confocal laser microscopic observation after 96 h cultivation, it was found that albumin production preferentially occurred in the center of the spheroid. The albumin production of the cells that adhered to PBMA was sparse. The amount of albumin production per unit cell that adhered to PMBL1.0 was determined by ELISA and was significantly higher than that which adhered to PBMA. Long-term cultivation of HepG2 was also performed using hollow fiber mini-modules coated with PMBL1.0. The concentration of albumin produced from HepG2 increased continuously for one month. In the mini-module, the function of HepG2 was effectively preserved for that period. On the hollow fiber membrane, spheroid formation of HepG2 cells was also observed. In conclusion, PMBL1.0 can provide a suitable surface for the cultivation of hepatocytes and has great potential for producing reliable bioartificial liver (BAL) devices.

Piezoelectric ink jet processing of materials for medicaland biological applications

Many advanced medical and biological devices require microscale patterning of cells, proteins, and other biological materials. This article describes the use of piezoelectric ink jet processing in the fabrication of biosensors, cell-based assays, and other microscale medical devices. A microelectromechanical system-based piezoelectric transducer was used to develop uniform fluid flow through nozzles and to prepare well-defined microscale patterns of proteins, monofunctional acrylate ester, sinapinic acid, deoxyribonucleic acid (DNA), and DNA scaffolds on relevant substrates. Our results demonstrate that piezoelectric ink jet deposition is a powerful non-contact, non-destructive additive process for developing biosensors, cell culture systems, and other devices for medical and biological applications.

Effect of CaF2 and CaO Substituted for MgO on the Phase Evolution and Mechanical Properties of K‐Fluorrichterite Glass Ceramics

Chain silicate glass ceramics based on K‐fluorrichterite (KNaCaMg5Si8O22F2, KFR) have potential for use in restorative dentistry and biomedical applications because they may be cast to shape and, when cerammed, have high biaxial flexural strength and fracture toughness. Excess CaO in canasite‐based chain silicate compositions is known to enhance their bioactivity. Therefore, two new glass ceramic compositions have been fabricated with 5 mol% CaF2 (Glass A) and 5 mol% CaO (Glass B) substituted for MgO in the KFR formula unit. The phase evolution of Glasses A and B was studied in detail using X‐ray diffraction and transmission electron microscopy. In addition, their mechanical properties were assessed. For Glass A, the fracture toughness (FT=2.66±0.02 MPa·m1/2) and biaxial flexural strength (BFS=227.3±24.5 MPa) were optimized for samples heat treated at 900°C for 4 h. In Glass B, however, the best FT (2.08±0.02 MPa·m1/2) and BFS (217.4±4.4 MPa) were obtained at 950°C. In view of their excellent mechanical properties and castability, Glasses A and B are considered potential candidates for fabrication of custom medical devices in restorative dentistry and moderate load‐bearing reconstructive bone surgery.

The use of rhodamine 6G and fluorescence microscopy in the evaluation of phospholipid‐based polymeric biomaterials

A technique is described that allows the staining and subsequent visualization of polymers that contain the phosphorylcholine (PC) group. These materials are useful as bulk materials or coatings for the fabrication of medical devices. The staining method employs rhodamine 6G, which can be simply and rapidly applied to the polymer coating and imaged using fluorescence microscopy. The specificity of the staining for the PC polymers makes this technique suitable for the evaluation of a wide range of substrates and provides qualitative information on coating uniformity, coverage and morphology. It can be used to examine the durability of, and defects in, the coating. Statistical analysis of the fluorescent intensity by measuring the pixel value during imaging can allow for the method to be used as a quality control tool.

Quantification of initial adhesion of Enterococcus faecalis to medical grade polymers using a DNA-based fluorescence assay

This paper reports on the use of a DNA-based fluorescence assay to study and quantify the initial interactions of the uropathogen Enterococcus faecalis with different polymers commonly used for the fabrication of medical devices and implants, including polyurethane (PU), silicone (SI), high-density polyethylene (HDPE), polyamide (PA), poly(methyl methacrylate) (PMMA) and polytetrafluoroethylene (PTFE). To follow the kinetics of E. faecalis adhesion, polymer samples were incubated in bacterial solution for various times and the relative concentration of adhered bacteria was obtained using two methods: commonly used CFU plate counting and a DNA quantification assay. Results obtained from DNA-based fluorescence assays showed that E. faecalis adhesion on PU is 3-times higher than that on PTFE following exposure to bacteria for 180 min. Neither surface wettability nor surface roughness of the studied polymers was found to correlate with E. faecalis adhesion, suggesting the involvement of much more complex adhesion mechanisms of bacteria onto surfaces. SEM micrographs of adhered bacteria illustrated that adhesion was different depending on the type of polymeric substrate: adhesion on PU samples was characterized by the aggregation of bacterial cells in dense clusters, as well as by the presence of fimbriae between cells and the substrate, which could explain the high adhesion to PU compared to the other polymers. This work demonstrated that the bacterial adhesion to polymers occurs at an early stage of the contact and suggests that the initial adhesion stage should be controlled, in order to prevent subsequent biofilm formation and, thus, reduce the risk of implant-associated infections.

Tensile Strength and Pseudo-elasticity of YAG Laser Spot Melted Ti-Ni Shape Memory Alloy Wires

In order to investigate the applicability of laser micro welding to the fabrication of medical devices, Ti-Ni shape memory alloy wires with pseudo-elasticity were micro spot melted by using YAG laser. By changing the melting parameters, such as laser power or pulse duration, the evolution in microstructure, tensile strength and pseudo-elasticity was investigated. Melted metal width decreased with decreasing the input energy and pulse duration. The microstructure of melted areas was cellular dendrite structures and that of heat affected areas was grown cell structure with a cell size of about 3∼10 μm. Tensile strength of spot melted wires was 30% lower than that of base metal, and the fracture occurred in melted areas with a brittle fracture surface. Although melted areas and heat affected areas did not show a pseudo-elasticity due to the larger grain size, minimizing the width of melted metal improved the overall pseudo-elasticity of spot melted samples. For the sample wires that were prepared by spot melting of cold rolled wires and by the subsequent heat treatment for shape memorizing, the pseudo-elasticity was improved because heat affected zone recrystallized to form fine grains.

In vitro biocompatibility assessment of sulfonated polyrotaxane-immobilized polyurethane surfaces.

Sulfonated polyrotaxanes (PRx-SO(3)'s), in which sulfonated alpha-cyclodextrins (alpha-CDs) were threaded onto the poly(ethylene glycol) (PEG) segments in a PEG-b-poly(propylene glycol) (PPG)-b-PEG triblock copolymer (Pluronic) capped with benzyloxycarbonyl (Z)-L-phenylalanine (Z-L-Phe), were prepared as a novel surface-modifying biomaterial. Surface modification of the polyurethane (PU) was carried out by blending the PRx-SO(3)'s with a PU solution, followed by solution casting. The incorporated PRx-SO(3)'s led to the enhanced hydrophilicity by changing the surface properties of the PU matrix. Modified PUs showed the stable entrapment of the PRx-SO(3)'s with little extraction into water and enhanced mechanical properties after exposure to water compared to the PU control. The incorporated PRx-SO(3)'s repelled the proteins and kept them from closely approaching the surface areas, prevented platelet activation by thrombin, and effectively repelled bacteria. These results suggest that both the supramolecular structure of the polyrotaxanes and exposure of the sulfonated groups onto the surfaces contribute to these phenomena. Thus, surface modification with PRx-SO(3)'s is suggested to be useful for the fabrication of biocompatible medical devices.

E. faecalis ADHESION ON MEDICAL GRADE POLYMERS

The aim of this study is to compare the initial interactions of Enterococcus faecalis, an uropathogen responsible for catheter-associated infections, with different polymers including polytetrafluoroethylene (PTFE), high-density polyethylene (HDPE), polyurethane (PU), and polymethylmethacrylate (PMMA), which are widely used for the fabrication of medical devices and artificial organs. To follow the kinetics E. faecalis adhesion, polymer samples were incubated at 37°C in bacterial solution, removed from this solution at pre-determined times, and then bacterial concentration on the surface was obtained. Moreover surface hydrophobicity, surface free energy, and surface roughness of the polymers were studied to investigate the parameters influencing bacterial adhesion. Preliminary results of the adhesion kinetics studies suggest that bacteria adhere quickly to the polymer surface independent of polymer composition; the adhesion occurs during the first 45 minutes. Although bacterial adhesion to PMMA occurred as quickly as to the other polymers, elapsed-time studies showed that PMMA seems to be more resistant to E. faecalis adhesion. Contact angle and surface free energy measurements showed that E. faecalis adhesion was lowest on the most hydrophilic and the most energetic surface. Further studies are required to determine if a correlation exists between surface characteristics and E. faecalis adhesion. AFM analyses indicated that all polymers possess a smooth surface with a mean roughness in the range of nanometres. This study suggests that the influence of the bulk properties of these materials is more significant than their surface roughness on bacterial adhesion.

Surface engineering of biomaterials with plasma techniques

In this study, 3 types of plasma techniques, i.e. plasma modification, plasma deposition and plasma followed by grafting reaction, are used for the fabrication of tools, medical devices and biomaterials. Depending on purpose, bioadhesion of cells and biomolecules is either looked for or avoided. Since the mechanisms of bioadhesion depend on the characteristics of the surface (hydrophilic or hydrophobic), modifying the surface by a treatment will alter the bioadhesion. These treatments are developed for the anti-fouling process, the sterilisation and the improvement of the formation of biofilms. They have also proved useful for the synthesis of biomimicking devices.

Protein profiled features patterned via confocal microscopy

Protein patterns were printed using conventional microlithographic materials in a bilayer arrangement and unconventional exposure tools. The bilayer resist stack consisted of a lower poly(tert-butyl methacrylate) layer and an upper diazonaphtoquinone/novolak layer. The protein features were printed in either ‘contact printing’, or ‘step and repeat’ mode. The latter printing mode can be managed in a flow-cell consisting of a standard microscope slide and cover slip, spaced apart by about 20 μm, as follows: (i) the exposure step is carried out in the cell using focused 488 nm beam of a confocal laser scanning microscope; (ii) the development step is performed by flowing the photoresist developer through the cell; (iii) the selective deposition of the protein (FITC-labelled avidin) is achieved via the flow of the protein solution through the cell until a desired contrast has been reached; (iv) the control of the process is assured using on-line monitoring of the photo-activated red fluorescence of the developing resist layer, and of the green fluorescence of the FITC-protein patterns, respectively. The protein printing technique uses equipment routinely available in biological laboratory. The ‘step and repeat’ patterning yields high and controllable resolution. The process can be applied in the fabrication of medical microanalysis devices.

Metallocene Polyethylene Films as Alternatives to Flexible PVC Film For Medical Device Fabrication

Metallocene Polyethylene Films as Alternatives to Flexible PVC Film For Medical Device Fabrication

Biomaterials availability in the U.S.

Slowly but inexorably the commodity materials that constitute over 95% of implantable devices are being withdrawn from the medical market. U.S. manufacturers operate on accumulated reserves and therefore are reluctant to say precisely when they will stop fabrication. Nonetheless, “thousands and perhaps millions of people [are] at risk of not being able to receive the most commonplace medical treatments1: vascular grafts, cardiac valves, hip joint prostheses, hydrocephalus shunts.” What is the problem? Companies that supply materials for, or components of, medical devices have stopped selling these essential ingredients to U.S. manufacturers of medical devices. Manufacturers, who typically have maintained large stocks since the unit cost of procuring raw materials is low compared to that of validating each new batch, are approaching the end of their reserves. The suppliers (typically multinational chemical companies one to three orders of magnitude larger than device manufacturers) have made the eminently rational decision to exit the U.S. market because they have been joined in expensive lawsuits related to allegedly defective products, such as temporomandibular joint (TMJ) prostheses and silicone breast implants. U.S. legal precedence allows an individual who has suffered bodily injury from a commercial product to sue all parties involved in the manufacturing of the product.2 In the case of medical devices, this doctrine has incriminated the suppliers of standard commodity materials, such as Dacron, Teflon, Delrin, and Silastic as well as standard engineering components used in the fabrication of medical devices. Suing DuPont or Dow Chemical for the failure of a prosthetic TMJ or a breast implant is a bit like suing U.S. Steel in the case of a car crash, or Texaco in the case of an automobile fire. Guilt by association. U.S. Steel supplied the raw metal from which the automobile was fashioned and Texaco the gasoline that fueled the fire. Similarly, Dacron yarn is essential for weaving or knitting large-diameter vascular grafts, Silastic is still the material for choice for constructing hydrocephalus shunts, and Teflon powder is critical to the manufacture of pacemaker batteries. None of these materials is the device. Because each implant contains only a few cents worth of any of these polymers, the sale of polymers to medical-device manufacturers represents an infinitesimal part of the market for polyethylene terephtalate, silicone elastomers, or polytetra-fluoroethylene. For example, the total sales of Teflon for TMJ implants were less than $2,000. In contrast, the annual cost to DuPont of defending itself against the lawsuits related to the TMJ (which it has won in all cases) has been hovering around $8 million! Therefore we have a perfectly understandable reason for American suppliers to refuse to deal any further with the U.S. medical-device industry, for overseas suppliers to adopt the same line of conduct, and for U.S. manufacturers to move fabrication abroad and de-emphasize innovation in the U.S. As a result, tens of thousands, and later perhaps millions, of U.S. citizens are at risk of not receiving some commonplace and effective medical treatments.3 In 1994, 14 specialty societies concerned with the availability of materials for medical devices formed the “Biomaterials Availability Coalition” to investigate means to avoid the looming crisis. The coalition's objective was to assist in the formulation of legislative remedies, inform the scientific and clinical community, and be the advocate of patients. At its behest, a Biomaterials Availability Act was introduced in Congress in 1995, derailed, reintroduced in 1996 by Senators J. Lieberman (D-CT) and J. McCain (R-AZ), merged for convenience with the Product Liability Reform Act (HR 956), passed by both houses of Congress with comfortable majorities, then vetoed by President Clinton.

Giant Cell Myocarditis Associated with Silicone: An Unusual Case of Biomaterials Pathology Discovered at Autopsy Using X-Ray Energy Spectroscopic Techniques

Silicones, used extensively in the fabrication of medical devices because they were presumed inert and biocompatible, are now well-recognized inducers of localized granulomatous inflammation. Silicones less commonly are also associated with more complex clinico-pathologic entities. In this communication, the authors present a case of a patient on chronic hemodialysis involving tubing probably fabricated from silicone rubber who died from a giant cell myocarditis associated with silicone rubber. This case is presented to expand the interpretive paradigm of human pathology and underscores the need for pathologists to consider medical-device associated phenomena in the differential diagnosis of clinical specimens.

Toxicology of Biomedical Polymers

This paper deals with the various types of polymers, used in the fabrication of medical devices, their diversity of applications and toxic hazards which may arise out of their application. The potential toxicity of monomers and the various additives used in the manufacture of biomedical polymers have been discussed along with hazards which may arise out of processing of devices such as sterilization. The importance of quality control and stringent toxicity evaluation methods have been emphasised since in our country, at present, there are no regulations covering the manufacturing and marketing of medical devices. Finally the question of the general and subtle long term systemic toxicity of biomedical polymers have been brought to attention with the suggestion that this question needs to be resolved permanently by appropriate studies.

Filler material in medical-grade silicones

Medical-grade silicone rubber is a widely utilized biomaterial. As is the case for most rubbers, fillers are used to give additional strength to the polymer. The nature of the filler is of interest in the development, fabrication and improvement of medical devices where blood and tissue compatibility may be altered by submicroscopic structure and phase distribution. The medical-grade silicone rubbers are of two types, heat-vulcanizing and room-temperature-vulcanizing (RTV).The filler used in heat-vulcanizing types is fumed silica of a small particle size of the order of 0.03 µm and smaller (0.007 µm; 0.012 µm; Cab-0-Sil®, Cabot Corp., Boston, MA 02110). It is made by a vapor phase process (hydrolysis of silicone tetrachloride at 1100° C ), producing a colloidal amorphous silica (SiO2). It is generally classified as a fumed silica due to its production at a high flame temperature. Fume-process silicas give the highest degree of reinforcement of silicone rubber compared with finely divided silicas made by a wet process (aerogels), or with diatomaceous earth.