Medical Device Link.

MATERIALS

Take control of the surface

The use of self-assembling monolayer end groups (SAMEs) is an emerging two-dimensional nanotechnology for controlling the surface properties of medical devices made from polymers. SAME technology is a more highly evolved version of an earlier approach called surface modifying end groups (SMEs).¹ Although SMEs are surface active, they were not specifically designed to influence self-assembly in the surface region. SAMEs utilise surface activity and self-assembly to control the chemistry and the nano-structure of a polymer’s surface. SMEs have been used to make biocompatible surfaces with improved biostability, better thromboresistance and controlled wettability. SAMEs can do the work of SMEs, but they can also be used to tether bioactive moieties to a surface that is composed of an ordered array of spacer chains with head groups that react with the bioactive species. Surfaces of this type can be designed to produce specific surface interactions, for example, selectively binding proteins, pathogens or cells from blood.

Bulk polymer properties are determined largely by the polymer’s backbone structure and chemistry, while the terminal SAME groups appended to the backbone chain dominate surface properties. SAMEs become an integral part of a polymer during synthesis and provide a robust, built-in surface modifier for the polymers to which they are attached. This opens up a new world of possibilities for medical devices and prosthetic implants.

The technology explained SAMEs are composed of at least three parts: a chemically reactive group to bond them to the polymer as it is being made; typically, a hydrophobic spacer chain, which is able to self-assemble at the surface of articles made from the polymer; and a head group with specific surface chemistry.

Figure 1: Schematic representation of a model SAME in the surface of a polyurethane. Here, simple C18 or stearyl goups are used in the manufacture of polycarbonate urethanes (Bionate II) with SAME technology. Excess end groups remain below the surface in the bulk and can replace end groups lost from the surface, for example by abrasion. This self-healing property is not available in monolayer thick topical coatings applied after device/component fabrication. (click image to enlarge)

During the chemical synthesis of a polymer, its long molecular chain is terminated with lower molecular weight end groups that can move to, and assemble in, the polymer surface. The whole process is spontaneous, driven by the tendency for liquids and solids to minimise their interfacial energy. Anything subsequently made from a specific end-group-modified polymer will exhibit similar surface characteristics. Polymers with different backbones but identical SAMEs will also present similar surface chemistry and architecture (Figure 1).

End groups are more mobile than the polymer backbone chains, in part because they are usually tethered to the backbone by a single, flexible chemical bond. The terminal end or head group of the surface modifier is highly mobile. This mobility allows the end groups to diffuse through the bulk and concentrate at the polymer surface. In SAMEs, the self-assembling spacer chains create a well ordered surface region with head groups making up the outermost monolayer. This region can be extremely different from the chemistry and structure of the polymer that is below the surface, as confirmed by surface-sensitive characterisation methods such as Sum Frequency Generation (SFG) spectroscopy.²

The diffusion process occurs spontaneously. Simple hydrophobic end groups may diffuse toward an air interface, and hydrophilic end groups may enrich a polymer surface when exposed to an aqueous environment such as body fluids. SAME technology utilises specific hydrophobic or hydrophilic spacer groups with head group chemistry chosen for the particular application. The spacer groups will self-assemble at the surface through hydrophobic or specific interactions and thus present the head group as the all important outermost monolayer of the polymer. This is the region that interacts with the biological interface.

Application examples

Figure 2: SFG spectra comparing Bionate with Bionate II polycarbonate urethanes with C18 SAME technology (left). There are no methyl groups on the surface of unmodified Bionate (red/left). Methyl head groups on the polymer with the C18 SAME groups dominate the surface (black/left). Adding the processing aid bisstearamide wax can also produce a methyl-rich surface, but unlike the SAME groups, it is free to migrate out of the polymer during use. (See Reference 2 for a description of SFG) (click image to enlarge)

In device applications involving blood or tissue contact, optimum performance requires control of surface properties, for example, for modulating protein adsorption, tissue response, device centred infection and biostability. When specifying a biomaterial for a medical device the surface and bulk properties must therefore be considered. Once the (bulk) mechanical properties are specified and a polymer is chosen, the surface can be optimised by selecting an appropriate SAMEs chemistry and structure. For example, a passive group such as polyethyleneoxide (PEG) that is biocompatible could be used, or a chemically reactive amine head group can be chosen for subsequent binding of peptides, polysaccharides or proteins to create the desired surface.

The choice of the head groups may be determined empirically from in vitro or ex vivo experiments using the self-assembling monomers favoured by researchers such as alkane thiols adsorbed onto gold plated substrates. The actual device, however, must be constructed from a much more biostable, structural material: the polymer containing the SAME technology.⁴

Nonleaching processing aid/surface modifier

Most industrial grade thermoplastics polymers contain low molecular weight processing aids. One common processing aid used in medical device manufacturing is a bisstearamide wax. SAME technology can produce a self-assembling, “non-fugitive” alternative to N, N’-ethylene bisstearamide, also known as Advawax (Rohm and Hass, www.rohmhaas). Advawax is used at 0.25 to 5 wt % in many polyurethanes. It is a reaction product of stearic acid and ethylene diamine, has a molecular weight of 593 D and melts at 138 ºC. It lubricates the polymer chains in the melt, reduces polymer self-adhesion and improves mould release of configured articles. More significant is the fact that the alkane chains on Advawax constitute the blood or tissue-contacting surface of most medical grade polyurethanes. Although surfaces rich in C18 groups have been associated with increased albumin adsorption and favourable blood–materials interactions, the low molecular weight of Advawax allows it to leach from polymer surfaces, which is a serious drawback in chronic implants.

A unique combination of toughness and inherent biostability makes aromatic thermoplastic polycarbonate urethanes (TPCU) candidates for use in many chronic implants. Existing applications include hip and knee joints, prosthetic spinal discs, dynamic spinal fixation components and neural stimulation leads, all of which are made by extrusion or moulding from the melt. Batch synthesised Bionate TPCU (DSM PTG, www.dsmptg.com) is made without processing aids and is often difficult to melt process. Melt viscosity can be significantly reduced and processing improved by covalently binding C18 SAME groups to TCPU during initial synthesis. Covalently bonded C18 end groups can provide permanent C18 surface modification, high strength, improved surface smoothness and possibly enhanced albumin adsorption³ on TPCU tubing made by melt extrusion, a processing method commonly used in medical device manufacturing (Table I).

In addition to providing improved processing and desirable surface chemistry and finish, C18 chains can be considered as models for more complex SAMEs described below that incorporate biologically active head groups potentially useful in diagnostic, therapeutic and prosthetic applications of biomedical polymers.

Antimicrobial surface modification

Table I: Property comparison showing additive-free Bionate thermoplastic polycarbonate-urethane with and without C18 SAMEs. End groups preserve the properties of original base polymer. The increased melt flow rate indicates improved thermoplastic processing, and low water and chloroform extractables. (click image to enlarge)

Antimicrobial topical coatings are used on urinary catheters and on other devices and implants to reduce infections.⁵ Virtually any foreign object in the body can become infected. This is particularly true for percutaneous devices, which create a tract for microbes to migrate into the body from the skin surface. For this reason antimicrobial coatings are of great interest. However, coatings can be prohibitively expensive for low cost disposables. This may be true even when the incidence of infection related morbidity is known to be a significant problem, as in the case of the ubiquitous intravenous catheter.
Polymers with SAME technology incorporating antimicrobial head groups may be an answer to this problem. Even mixed antimicrobial head groups may be used for defence against different pathogens.

Heparin based anticoagulant surface modification

The contact of blood with polymer surfaces can trigger thrombosis. Blood clots formed on a device surface may detach to create emboli in the flowing blood. Emboli can lodge in blood vessels downstream, blocking blood flow to tissue and cause strokes, heart attacks and other serious circulation problems.

Heparin is a naturally occurring sulphated glycosaminoglycan with an extremely high negative charge density. It is a unique carbohydrate with millions of possible polysaccharide sequences along its backbone that can act as specific binding sites. Its most common clinical use is as a systemic anticoagulant where it binds the enzyme inhibitor antithrombin III, inactivating thrombin and factor Xa involved in thrombosis. When immobilised on polymer surfaces, heparin can reduce or prevent surface induced thrombus formation. This is especially important on devices that have high surface area such as dialysers and oxygenators.

Using SAME technology, polymers can be created that have built-in heparin binding capability, potentially simplifying the heparinisation process and making it economical in a wider range of devices. At least two applications of surface bound heparin using SAME technology are being investigated: a low cost alternative to expensive end point attached heparinisation schemes for common blood contacting devices; and an application in which the immobilised heparin is optimised as an affinity substrate for therapeutic or prophylactic use. These applications involve direct blood contact. Heparin based affinity therapy depends on heparin’s anticoagulant properties for safety and its ability to bind cytokines and pathogens (viruses, bacteria and parasites) for efficacy.

One ambitious use of immobilised heparin is in a cartridge based treatment for sepsis/toxic shock. This condition can be resistant to drug therapy and has a high mortality rate. Heparin based affinity therapy may provide an alternative approach.

Spreading disease via blood transfusions remains a real risk today. Small cartridges containing immobilised heparin may also be of value for blood banks, which would filter collected blood through the devices to provide a healthier blood supply.

Passive nonthrombogenic surfaces

The difference between an active, antithrombogenic surface and a passive surface is that the antithrombogenic surface almost always contains heparin, which interferes with the complex series of reactions that result in surface induced thrombosis. Many long term clinical applications have the best patient outcomes when no response is created from blood contact or, more precisely, there is no clinically intolerable response. This applies to prosthetic devices such as artificial heart and ventricular assist devices that may be used in the body for months or years. However, any application with the need for inherent blood compatibility would benefit from this technology. Here, the benefit of SAME technology is longevity, which may exceed that of certain heparin immobilisation strategies. Candidate spacer/head groups include C18, methyl-terminated polydimethylsiloxane, and methyl terminated PEG or other hydrophiles.

Because SAME technology creates molecular monolayers at the surface, only small quantities (as a per cent of the total polymer weight) of end group molecules are needed to cover the surface with a near complete overlayer. End groups incorporated into a polymer during synthesis are added in excess, relative to the minimum needed for surface coverage, and remain “in reserve” in the polymer bulk. For this reason, if an end group is lost from the surface, it is possible for it to be replaced from the reservoir of end groups remaining below. This is a distinct advantage over monomolecular surface modifications applied as coatings.

Reduced nonspecific protein adsorption

The performance of many devices is degraded when proteins accumulate on the surface. However, certain surfaces can discourage adhesion of protein. PEG is one well-known example.

Implanted sensors can benefit from this type of built-in surface modification. Proteins accumulating on the surface can skew or block the signal to the sensor. A glucose sensor is an example where the selectively permeable membrane has a precisely designed permeability. The chemistry controls the rate of oxygen and glucose permeation through the membrane
to an electrochemical reaction that creates a signal. If the permeable membrane becomes covered with proteins from the body, it can degrade the signal over time.

Using a SAME monolayer at the polymer surface may reduce potential sensor fouling while maintaining the required permeability of the membrane layer underneath. The membrane polymers for the sensor can be specified by the device manufacturer and then built into the sensor. The outer surface of the membrane can be controlled by the SAME technology, while the permeability of the inner membrane is controlled mainly by the backbone of the membrane polymer.

The future for SAME technology

Optimal bulk properties and precisely controlled surface chemistries are critical to developing sophisticated polymer based medical devices. Bulk properties provide structural integrity and determine properties such as tensile strength, flex life and permeability. However, it is surface chemistry that determines biological interactions at the biointerface. SAME technology offers seamless surface modification during the manufacturing process, which provides a robust, built-in surface chemistry.

Although ideally suited to so-called step growth polymerisation, SAME technology can be applied to virtually any polymer. For this reason, it is a candidate for use in many biomedical disposables and in implantable devices and prostheses. It is potentially useful in any application in which tailoring of surface properties can improve performance or reliability. Because SAME surface modification is built into the polymer itself, not painted on after the device is made, the potential is broad and it should prove to be a major advance in the use of polymers as biomaterials.

Robert S. Ward is President Chief Executive Officer at DSM PTG, Part of DSM Biomedical, 2810 7th Street, Berkeley, California 94710, USA, tel. +1 510 841 8800, e-mail: rward@polymertech.com, www.dsmptg.com