Biomaterials for MEMS

Application of MEMS in Drug Delivery 159

as the diffusion through the fibrous capsule towards the active sensing surface is

either reduced or absent.

11,57,58

Second, limited capsular vascularity results in poor

drug perfusion, leading to significant increases in the delivery time, in the best of

circumstances, and possible accumulation of drug within the local environment

with limited/absent distribution.

59

When tissue represents the implantation site, the surface exposed BioMEMS

material directly interacts with the local biological environment being subject

to sustained attack and degradation by tissue, such as hydrolytic enzymes and

monocyte-induced free radical damage (Fig. 7.6).

13

Aside from affecting BioMEMS

mode of action, there may be local toxicity effects of surface degradation products

that have to be considered.

13

7.3.3 Hemocompatibility and Effect on Biofunctionality

Placement of BioMEMS drug delivery systems in the blood stream leads to adsorp-

tion of proteins on the device surface, particularly fibrinogen and von Willebrand’s

factor, which can lead to adhesion and activation of platelets, the first step in the

initiation of thrombus on the surface of any implanted material/device.

60

The coagulation cascade is initiated by platelets deposition, recruitment, and

degranulation at the surface of the biosensor, which is, then, amplified by leuko-

cyte and erythrocyte deposition. In combination with Factor XII, the initiated

coagulation creates a dense biofouling layer that could significantly diminish the

intended device action. Further, surface coagulation occurs even in the presence of

an anticoagulant. In addition, intravascular placement of devices leads to distorted

haemodynamic flow, with local vortex formation. Similar to the intravascular

effect of an anchored thrombus, the intravascular presence of a BioMEMS results

in elevated shear forces and collisions by platelets that aggregate onto the sur-

face. Over time, platelet aggregation leads to thrombus formation and possible

thromboembolism, if the device is maintained in the intravascular environment for

extended periods of time. In spite of all these apparently staggering drawbacks, it

is the field of implantable stents for the treatment of cardiovascular disease which

leads the commercialization of MEMS based therapies.

7.4 BIOMEMS DESIGN PARAMETERS AFFECTING

BIOCOMPATIBILITY AND BIOFUNCTIONALITY

7.4.1 Material selection

Traditionally, the substrate used in BioMEMS fabrication has been silicon, how-

ever, presently, the material selection has been significantly expanded to include

glass, metals (titanium), and polymers. The alternative material selection in the

fabrication of BioMEMS has been prompted by the poor biocompatibility dis-

played by silicon compared to materials such as titanium, polymethylmethacrylate

SO13997_text.indd 167SO13997_text.indd 167 26/01/2011 3:50 PM26/01/2011 3:50 PM

160 G. Voskerician

(PMMA) and polydimethylsiloxane (PDMS), in addition to the silicon’s limited

versatility of mechanical properties.

The question then arises — what is the acceptable level of biocompatibility

which should be displayed by the component materials of a BioMEMS? The simple

answer to such question rests with the critical interactive aspect of each device with

the local biological environment, the contacting surface. It is the device contacting

surface that is responsible for transducing its structural make-up to direct or

influence the response of proteins, cells,andtheorganismasawhole. Thelocal

biological environment reads the surface structure and responds to it. Certainly,

the task becomes more difficult in the case of devices which release bi-products

locally, leach substances that could affect the local or systemic environment or

expose, as a result of their mechanism of action, a “new” contact surface to an

active inflammatory and wound healing site. Specific to BioMEMS developed

for drug delivery applications, following drug release from reservoirs, “new”

surfaces are exposed to the local environment; indeed, for example, silicon walls

of an empty reservoir, now exposed, represent a “new” surface to the biological

environment, thus, inducing an associated inflammatory response(Fig. 7.7).

The comparative analysis on the effect of “new” surface exposure must be

evaluated within the context of the miniaturized device and not normalized to

an irrelevant macroscopic control device of similar surface contact material, yet, of

significant size disparity. This approach becomes even more important in circum-

stances where arrays of BioMEMS reservoirs are opened all at once, exposing to

the local biological environment a large “new” contact surface (Fig. 7.8).

56,61

The

newly exposed area will induce a typical staged inflammatory response initiated

by protein adsorption and cellular migration and activation, thus, enhancing the

ongoing inflammatory response subsequent of the initial injury and placement of

the device in the local biological environment.

Figure 7.7. BioMEMS multi-array prototype. The membrane of a drug sealed reservoir

had undergone dissolution. Following the release of the drug from the reservoir, the inner

surface of the reservoir is now exposed to the local biological environment (top view).

SO13997_text.indd 168SO13997_text.indd 168 26/01/2011 3:50 PM26/01/2011 3:50 PM