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Literature Review

Challenges in implantable bioMEMS: Biocompatibility


Constantino Migulez Pea

MSc Smart Systems Integration, Heriot-Watt University

Abstract: The biggest challenge regarding the packaging of implantable devices is the
biocompatibility of the materials exposed to the biologic medium, there is no perfect
biocompatible material so far discovered. In order to assure the reliable and safe
operation of the implant in the long-term, effects such as protein adsorption and
denaturation, surface fouling, corrosion and immune response reactions that affect the
operation of the device must be carefully evaluated.

Introduction
The development of sophisticated implantable biomedical devices is allowing medicine to restore function, improve wellness and
monitor vital constants in patients. These developments have been made possible by the research on new material compositions,
microfabritation technologies and the biological reactions of the human body to the presence of these materials.[1]

Microfabricated implantable devices can interact with the surrounding tissue with high precision and have long -term operation
inside the organism. Micro Electromechanical Systems (MEMS) implantable devices have applications within a wide range or
areas in the medical field. The major advantages of these systems are their low dimensions, reduced energy consumption,
increased sensitivity and selectivity and, in general terms, extended capabilities in comparison with the previo us generation of
macroscale implants. An implantable MEMS device comprises a set of sensors or actuators in combination of integrated circuits
for data processing and, in newer systems, for communication with the exterior. MEMS can be used for assistance during
surgery, monitoring of physiological data, long-term implants or drug delivery.[2][3]

In general terms, the main requirements for the design and fabrication of implantable MEMS are reduced size, which reduces
power consumption, weight, inflicted trauma during implantation and reduced exposure of the body to foreign materials and the
subproducts they originate as a result of corrosion or wear. Another requirement mechanical resistance to stress and wear and
moisture penetration and hermeticity, the devices must be sealed and protected from the harsh environment that the body is in
order to guarantee a safe and reliable long-term operation, at the same time the encapsulation of the device must be able to
provide the system with a feedtrough to the exterior in order to actuate and sense the outer environment without exposing the
body to hazardous materials. The device must operate under a maximu m allowable tempera ture in order not to damage the
surrounding tissues.[1][4][5]

The most challenging requirement on the design of implantable MEMS is biocompatibility. Biocompatibility is the ability of a
material to not interfere nor degrade the biological environment to which it is exposed to. Different materials present different
degrees of biocompatibility in relation to different biological environments. The materials used on the coating of the implan ts
must be chosen in accordance to the medium they are meant to be placed on and they must not be inflammatory, toxic,
allergenic, carcinogenic nor thrombogenic when place inside blood vessels, currently there has not been discover any material
which perfect biocompatibility which completely meets all these criteria, making this aspect of packaging for implantable
devices the most challenging area of research.[4][6][3]
Biocompatibility in implantable MEMS
The concept of biocompatibility implies how well a living body can adapt to the insertion of a foreign material, the lower the
need for the body to modify its functional attributes upon implantation, the higher the degree of biocompatibility the inserted
material has. When designing implantable devices on the human body, special consideration must be paid to the interaction of
the materials in contact with the surrounding tissue. When a foreign body is inserted into the organism it responds with several
reactions which either, affect to the performance of the device and pose a risk to the health. These effects can be avoided or
minimizing by paying special attention to the biocompatibility, which limits the packaging techniques and the materials that can
be used to fabricate the device.[1][2]

Biocompatibility is the biggest challenge regarding the packaging of implantable microsystems. A perfect degree of
biocompatibility between an biological and non biological material cannot be obtained.[2] This paper discusses the biological,
physical and chemical facets of the microscale and nanoscale interactions involved in the implantation of MEMS into the human
body.

This paper will review first different aspects related to the environment ins ide human body, secondly the temporal evolution of
an implanted device will be discussed, regarding the reactions that take place inside the organism since the first moment when its
inserted until the long-term evolution of the microsystem and how it is affected by the immune system, next, the interfacial
interactions between the artificial and biological s urfaces will be described, this will be followed by a description of the process
of protein adsorption and denaturation, its causes and its negative effect on biocompatibility. The following part will consider
how the reactions of the immune system to the implanted system and corrosion affect to the degradation of the system. And
finally, the biocompatibility analysis methods will be pointed out.

The environment inside the human body


The majority of the implants are located on the extracellular space which can be aqueous, soft tissue or hard tissue medium.
Some implants require the intracellular implantation such as the neuronal devices. A distinction between intracellular and
extracellular medium can be done here. In the intracellular environment, the cytoplasm, there is a higher concentration of
potassium, magnesium and calcium ions while the extracellular medium has high concentrations of sodium ions. The
intracellular system contains as well a high concentration of diverse types of molecules that intervene in the cellular metabolism
and can affect to the implanted device. Chloride anion is present in both environments which causes corrosion on metallic
materials, specially taking into account that the catalyzing effect of temperature inside the human body, which is 37C [2][7]

Examining the different biological fluids in the human body, blood has a high protein and glucose concentration, while proteins
are almost absent in urine which contains a strong concentration of urea. Tears and synovial fluid are similar to blood in glucose
concentrations. While all these biofluids have different molecular concentration profiles, water is present and the most
predominant element in all of them. Microorganisms are ubiquitously present among the human body, these include different
types of bacteria which live in the mainly within the gastrointestinal system with an extremely high concentration and other
bacterium and pathogens in other regions mainly associated with infective processes. The immune system provides several types
of responses against bacterial invasion, the insertion of a foreign material into the body, may favor the proliferation of pa thogens
on its surroundings, therefore it is of special importance that the materials used on the implant can resist bacterial proliferation in
order to avoid infection.[2][8]

These different characteristics of the diverse mediums in the human body determine the type of material that can be used for an
implantable device. For example, devices exposed to blood should be resistant to corrosion and protein adsorption or those
located in the intestine should be able to deter bacterial colonization. These considerations are of vital importance in aims of
providing the implant with biocompatibility characteristics that will guarantee the safe and reliable operation of the implanted
device in the long term.[2]

Biological processes related to the insertion of an implantable device in the human body
There are three main processes associated to proteins regarding the implantation of a foreign object into the human body, these
are protein adsorption in the interfacial surface, which may undergo a denaturation proces s in which their molecular structure is
altered leading to be recognized by the immune system as non -self, subsequently triggering an inflammatory response and other
biocompatibility related problems.[8]
Insertion of a device implies the breakage of tissue and blood vessels, the blood contains a coagulation mechanisms to avoid
leakage, which depends on the subtle balance of several reactions, if any of them is compromised by the foreign material, either
inhibiting coagulation or by triggering it when there is no need, it could provoke undesired effects such as thrombosis or
excessive bleeding.[2][8]

Blood is a heterogeneous fluid in which proteins and different types of cells coexist; these all elements react in different manners
to the presence of a foreign, larger object such as the implant. Being the proteins those which experiment the fastest diffus ion
among all of them, they are the first elements reaching the interfacial surface of the implanted device, this results in protein
adsorption which leads to the whole interfacial surface to be covered by proteins. As it was mentioned previously, there are many
types of cells present in the blood; the membrane of these cells is normally covered by many types of proteins and viruses, that
would react to those present on the interfacial surface of the implant. This is called surface rea ctivity and implies that some
specific chemical groups existing on the interfacial surface of the device may interact with the biological medium. The proteins
on the interfacial surface due to adsorption may create hydrogen bonds with cells in the bloodstream or bacteria, which once
adhered to the interfacial surface would secrete a series in insoluble biopolymers which would create a strong adhesion between
the implant and these cells. [9][10]

Biofluids have the potential to produce corrosion in the materials of the implanted device exposed to them, especially on metals.
Corrosion involves the release of toxic metal ions within the body and it can be produced in the long-term operation of the
device, leading to disease. For this reason, the design of the implant should estimate the lifetime biocompatibility of th e
packaging in order to avoid or address the future need for explanting the device.[11][12]

The biological non biological interfacing surface


The interfacial surface comprises three different elements, the artificial material, the biological matter of the s urroundings and
the particles attached to the surface of the implant, which are either proteins or cells. All these three components are disp ersed in
an aqueous medium. This part will describe how these particles behave and interact with the interfacial su rface.

The interactions between the proteins and cells attached to the interfacial surface and the artificial material can experimen tally be
quantitatively characterized with strength and sign. There other kind of particles present in the aqueous medium such as
osmolytes and ions which also participate in this type of interactions , mainly by binding to the surface of proteins. Similarly to
liquids, solids have also surface tensions and these tensions are the sum of two components, Lewis acid -base and Lifshitz van der
Waals interactions. While the second one is always of positive sign (attractive) and of a weaker magnitude, the first one can be
positive or negative.[2] [10]

The constitution of the interface by adsorption of proteins requires energy exchange (at a constant temperature and pressure),
which can be either gained or lost. Therefore, the interest is on the total variation of Gibbs free energy in the interface.
Considering the adsorption of proteins, if the energy at the final state has increased in respect to the initial state it mea ns that the
proteins have not been spontaneously adsorbed to the interface. Hence, the analys is is focuses on the sign of the variation of the
free energy during the adsorption process. This energy is called interfacial free energy and it is the sum of both the energy of the
biological elements interacting with the artificial surface and the cohes ive energy related to the polar aqueous medium.[2][7]

The degree of biocompatibility of a material can be estimated by calculating the net interfa cial energy, which indicates whether
or not the biological and artificial materials will adhere within the aqueous medium. If the sign of the net interfacial energy is
negative, this indicates a repulsive interaction and the possibility that the surface of the implant will repel proteins, it the sign is
positive it indicates that the implant is likely to be protein-coated. The magnitude of the net free energy indicates the strength of
this interaction, therefore if the net value of the free energy is near zero, whether if it is positive or negative, it only indicates a
weak interaction.[10]

Fig. 1Typical net interaction profile between an artificial implant material.[2]

As the distance between a protein or cell and the interfacial surface increases beyond certain distance, the energy of intera ction
decreases to zero. In the opposite side, as the distance within them decreases the energy of their interaction does not increase in a
linear manner, there is a point where an repulsive energy barrier exists, followed by a deep if the protein approaching the
interface has enough energy to s urpass this energy barrier, it would likely be adsorpted by the surface and experiment structural
changes which would make the adhesion process practically irreversible. This phenomena explains the actual challenge in
creating biocompatible materials that are able to resist protein adhesion due to the fact that, eventually, a device coated with a
highly hydrophobic material such as polyethylene would experiment protein adhesion on its interfacial surface. [2][10]
The inflammatory and the immune response
When the proteins are adsorbed in the interfacial surface of the implant, they are denatured, denaturation implies a change in the
spatial structure of the proteins, which can be now recognized as non self by the immune system, and therefore triggering the
undesired immune response in order to try to eliminate the foreign object. Since due to the dimensions of the implant it is
impossible to be eliminated, this results in a continuous inflammation.[8][9]

The cells of the immune system constantly present in the blood are the lymphocytes, macrophages and T lymphocytes. The last
ones have receptors for foreign sequences of aminoacids (peptides), when they detect one of these sequences they bind to them,
triggering the activation of the macrophages to phagocyte the foreign peptide. B lymphocytes generate antibodies that bind to
specific non self peptides and, in the same manner then tlymphocytes, they activate the macrophages which try to phagocyte and
destroy the foreign body. This reactions cause inflammation, since the foreign peptides form part of the biofilm in the interfacial
surface of the implant, it is impossible for the macrophages to phagocyte an element of that size, failing in their mission; the
immune system keeps producing more lymphocytes and macrophages, creating more inflammation and placing a metabolic
stress in the organism, and subsequently a series of related side effects.[2][8]

Corrosion and toxicity of the coating materials


Corrosion is influenced by the presence of water, temperature and electric potencials, therefore it is an aspect of es pecial
importance in implantable devices. The implants that must remain inside the body during decades must be packaged materials
very impermeable to water vapour such as glasses, ceramics or metals. The biological environment can produce corrosion in
every material, especially in metals due to anodic dissolution. Corrosion is a source of failure in many electronics systems. The
degree of corrosion that a metal may undergo within the human body can be evaluated by its positive oxidation potential, metals
which have a high positive potential in respect to the standard potential for the hydrogen electrode, are resistant to corrosio n.
Metals with high negative values for their oxidation potentials are prone to corrosion. Titanium is an exception of this because
even though it has a strong negative potential, it is covered by a relative thick film of oxide; nevertheless this layer could be
removed by wearing, exposing then the material the medium and subsequently causing corrosion of the material. [12][2][13]

During the process of metal corrosion, metallic ions are released into the body; some can interfere with biochemical reaction in
the organism. Hence, special consideration should be taken when using metallic material on the design of an implantable device
due the toxicity of released metallic ions.[12]

Several corrosion technniques have been used to characterize the corrosion of packaging of biomedical implants. The open
circuit potential is a value that indicates the corrosion potential of a metal immerse d in an electrolyte. This value is used to
predict the operation lifespan of the packaging within a corrosive biofluid environment. These technniques are the
Electrochemical Impedance Spectroscopy (EIS), which can characterize the materials by measuring t heir frequency response
properties. Another method is the Cyclic voltammetry (CV) which determines the window of operational potential or so -called
the water window. [7]

Fig. 2An anodic polarization curve measured on a Ti alloy in saline solution at 37C. The scan rate is 1 mV/second.

The stability in the long term operation of a metallic biomaterial is assessed in vitro by soak tests using pulsed stimulation. T he
materials are immersed in electrolytes at 37C or higher temperatures for cataly zing the process.[7]

Other aspects of biocompatibility


Some implantable devices are designed for operation under mechanical rubbing such us implants places in the joints or muscles .
In this case, it is important to consider the friction coefficients of the packaging materials in order to minimize wear. Wea r
involves particle release which may pose a health problem. For example, prostheses made of polyethylene typically generate
small particles, which behave as an adsorbent surface for proteins, are detected as non self bodies, triggering the immune
response mechanisms. Particles may present a degree of toxicity besides the undesired effects related to the immune response.
The biocompatibility of an implanted material in regard of the amount of small particles that it releases during operation is
directly related to its coefficient of friction. Some materials like monocrystalline sapphire, have very low friction coefficients,
and therefore, they release much fewer particles due to wearing.[2][8]

Another important aspect is the hydrodynamic biocompatibility, which relies in th e avoidance of interference within the implant
and the flows of different substances inside the body. For example, an implant located inside a blood vessel must not interf ere
with the blood flow inside the vessel, it should be implanted in such a way that it causes the minimum hydrodynamic
disturbance, which means being placed without altering the internal profile of the vessel, any alteration on it would affect the
efficacy of the immune system to combat inflammation. In order to prevent disturbances the implant could the embedded within
the cells that conform the structure of the walls in the vessel. Polarity of the material is another aspect to take into acco unt, the
device should have equal polarity than the tissue that it is embedded in order to enhanc e bonding to this material, for example
hydrogen bonds in case of a material of polar character.[2][8][6]

Cells tend to organize and align themselves in different patterns depending on their type, morphology, the surface they are o n
and the molecules present on the media. Cells also underg o morphological changes which are related to both morphological and
chemical characteristic of the substratum. This is a poorly understood area of the biocompatibility which still needs more
research to be carried out. In is expected that future research in nanotechnology will possibility the creation of surfaces with
atoms positioned in precise arrangements enhancing the control over the organization of around the implanted devices.[10]

Another issue regarding the cells where the implant is placed within is that cells always tend to modify their environment,
including the substrate, this means that they will release proteins that are adsorpted by the interfacial surface of the implant, and
therefore, controlling protein adsorption takes again special importance in regard of biocompatibility. [10]

Analysis and evaluation of biocompatibility


The quantitative assessment of biocompatibility of implanted devices presents one of the biggest challenges on this topic. It is
being characterized by the prolongation of the life expectancy of the patient and his subjective feeling of wellness; however it is
extremely difficult to quantify it objectively during operation because o f the lack of control over the implant once it is inside the
body. The methods currently used to asses biocompatibility of an implanted device include, analysis of the surrounding tissue ,
biopsy or inspection for corrosion in situ. Modelling of proteins as ellipsoids or spheres with certain surface properties for
computer simulations is a technique used to estimate adsorption of proteins, especially to study those systems which are
practically inaccessible. It nowadays presents some impracticalities such as extensive set up times and computer limitations.
Further improvement must be done in this field in order for these simulations to become a valuable tool in the prediction of
protein adsorption.[2]

A simulation method applied to measure protein adsorption in multicomponent fluids is the Random Sequential Addition (RSA) ;
this technique considers the relations between the free area on the interfacing surface for any type of protein to be adsorpted,
with the surface fraction covered by the proteins that are adsorbed. It has been observed that a protein that is irreversibly adhered
to the interface which is in contact with the same medium from which it originated, can exchange its plac e with another protein
in that medium, the mechanism of this process has not been identified so far but it seems to be related with the fast diffusion of
proteins in the interface surface.[2] The phenomenon described above applies to implanted devices which are exposed to a
complex biofluid such as blood; it contains many different types of proteins of diverse dimensions. An exchange of different
proteins occurs between the interfacial surface and the medium, this process is called the Vroman effect.[2][14]

The analysis for the degree of protein adsorption can be performed using non-labelling methods such as Surface Plasmon
Resonance (SPR) in metals and Optical Waveguide Lightmode Spectroscopy (OWLS) in ceramics. Analysis of adsorption in
complex mixtures is done by measuring the antibodies binding. Other methods that include labelling are radioactive and
fluorescence labelling, being the last one being the least perturbing one. The spatial arrangement of the adsorbed proteins can be
measured by atomic force microscopy (AFM) allowing the examination of adsorbents in the aqueous environment. Cell adhesion
to the interface can be analyzed by microscopy observation, with the convenience that cells can be examined without the need to
be fixed as it happens with electron microscopy. Electron microscopy is useful for studying the interfacial surface and bacteria
colonization, the drawback of this method is that the surface needs to be dehydrated and fixed.[2][14][15][16]

Conclusion
When a device is implanted within the human body, a biological non biological interface is created, the molecular reactions on
this interface determine the biological performance of the device. Materials used in the fabrication of an implantable device
should be carefully chosen , with the purpose of maximizing the biocompatibility of the implant, which means that it will not
cause any inconvenient effect on the organism.

The interactions on the interfacial surface can be characterized by using the surface tension concept and net free energy, allowing
to predict the behavior of different materials and proteins. Protein adsorption on the interface should be avoided, because it can
cause many undesired effects for the operation of the implant and a potential health risk since adsorpted proteins undergo a
denaturation process on the interfacial surface, which is a modification of the spatial structure of the protein; triggering immune
response mechanisms when they are recognized as non self molecules by the cells of the immune system. This immune response
leads side effects such as inflammation and an eventual rejection of the implant by the organism. Protein adsorption present of
the membranes of bacteria can facilitate infection. Biofluids are of a high corrosive nature, metals are especially prone to
corrosion, especially those with high anodic potential; corrosion liberates toxic ions in the organism that may produce a wide
range of side effects and disease.

The biggest challenge in biocompatibility is the in vivo quantification of the protein adsorption in the interface between th e
implant and the biological medium. There are methods for studying protein adsorption and corrosion on the interfacial surface
but, so far all of them require in situ analysis or biopsy of the implant. Future development of RF MEMS that will allow to
monitor these aspects of biocompatibility during in vivo operation.

Modelling and simulation of the behavior of the interface at a molecular level can estimate the type of interactions between the
implant materials and the biological environment, however this is an area that need further development in order to overcome
certain restrictions such as hardware limitations or excessive set-up times.

Future challenges on the biocompatibility of materials rely on improving the hydrophobic coating degree of coatings on implants
with the purpose of avoiding protein adsorption and prevent infection. So far the strongest hydrophobic material is polyethylene
glycol. Bacteria is capable of segregating biopolymers in order to increase their adhesion to the implant interface, development
of new alloying techniques to embed antibacterial metals in the interfacial surface is a promising path to create battery-resistant
coatings.

Currently there is not any material with perfect biocompatibility characteristics, furthermore, biocompatibility of a materia l is
subjected to the specific medium inside the human body that is going to be placed in, and therefore it is even a much greater
challenge to create materials suitable for implants in different areas of the body. For example, for the fabrication of nanob ots,
which would travel and operate among different media within the body.

Another challenge regarding the long-term operation of the implanted devices inside the human body is that, while the biological
tissues are constantly regenerating, artificial materials do not, and eventually they are prone to experiment failure, corrosion or
cause health problems in the host. The challenge is to create materials that could be subjected to restoration by the same
physicochemical mechanism of the living tissue.

Figures and tables

Fig. 1Typical net interaction profile between an artificial implant material.[2]


Fig. 2An anodic polarization curve measured on a Ti alloy in saline solution at 37C. The scan rate is 1 mV/second.

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