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Titanium Biocompatibility
Titanium was first introduced into surgeries in the 1950’s and used in dentistry prior to that a decade earlier. It is now extensively considered by medical professionals to be the metal of choice for prosthetics, internal fixation, inner body devices and instrumentation. Titanium is literally used from head to toe in biomedical implants. One can find titanium in neurosurgery, bone conduction hearing aids, false eye implants, spinal fusion cages, pacemakers, toe implants, and shoulder/elbow/hip/knee replacements along with many more. The main reason why titanium is often used in the body is due to titanium's biocompatibility and, with surface modifications, bioactive surface. The surface characteristics that effect biocompatibility are surface texture, steric hinderance, binding sites, and hydrophobicity (wetting). These characteristics are optimized to create an ideal cellular response.

Biocompatibility

Titanium is considered the most biocompatible of all metals due to its ability to withstand attack from bodily fluids, stay inert in the human body, be compatible with bone growth and stay strong and flexible during use. The materials ability to be resistant to body environments under stress, fatigue, and in crevice conditions is due to the protective oxide film that forms naturally in the presence of oxygen. The oxide film is highly adherent, insoluble, and chemically non transportable, preventing reaction from occuring.

Osseointegration interaction and proliferation

High energy surfaces induce angiogenesis during osseointegration ^[1]

Osseointegration is achieved through the high dielectric constant of titanium that gives it the ability to bind to bone and living tissue. The fact that titanium is able to physically bond with bone gives it an advantage over materials that require adhesives. Titanium implants last longer and require much higher forces to break the bonds that join them to the body.

Surface properties determine osseointegration

The surface properties of a biomaterials play an important role in determining the cellular response to the material. Changing the surface microarchitecture, chemistry, or energy can affect cell adhesion and proliferation. The microstructure and high energy surfaces of titanium implants induce its ability to produce angiogenesis during osseointegration. The titanium/tissue interface features enhance angiogenesis which accounts for controlling osseointegration. ^[2]

Surface Energy

Redox Potential

Titanium has many different standard electrode potentials depending on the oxidation state it is in. Solid titanium has a standard electrode potential of -1.63V. The larger the standard electrode potential, the easier they are to be reduced resulting in better oxidizing agents.^[3] As you can see in the table below solid titanium would rather undergo oxidation making it a better reducing agent.

Half Reaction	Standard Electron Potential (V)
Ti₂⁺ + 2 e^- → Ti(s)	-1.63^[3]
Ti₃⁺ + 3 e^- → Ti(s)	-1.21^[4]
TiO₂⁺ + 2 H+ + 4 e^- → Ti(s) + H₂O	-0.86^[5]
2 TiO₂(s) + 2 H⁺ + 2 e^- → Ti₂O₃(s) + H₂O	-0.56^[5]
Ti₂⁺(aq)/M₃⁺(aq)	-0.36^[4]

Surface Coating

The oxide film that forms due to corrosion becomes heterogeneous and polarized as a function of exposure to physiologic environments. ^[6] Factors that change during exposure include increased adsorption of hydroxyl groups, lipoproteins, and glycolipids. ^[6] This adsorption can change how the material interacts with the body and can improve biocompatibility. In titanium alloys such Ti-Zr and Ti-Nb, zirconium and niobium metal ions that are released due to corrosion are not released into the environment, but rather added to the passive layer. ^[7] The alloying elements in the passive layer add a degree of biocompatibility and corrosion resistance depending on the percentage of alloying elements found in the bulk metal prior to corrosion.

$\Gamma ={Q_{\text{ADS}}M \over nF}$ ^[8]
Protein surface concentration ( $\Gamma$ ) equation where Q_ADS is the surface charge density in C cm^-2, Mr is the molar mass of the protein in g mol^-1, n is the number of electrons transferred (in this case, one electron for each protonated amino group in the protein and F is the Faraday constant in C mol^-1.

$v_{\text{c}}={2\pi DcdN_{\text{A}}}$ ^[8]
Collision frequency equation where D = 8.83 × 10^-7 cm² s^-1 is the diffusion coefficient of the BSA molecule at 310 K,51 d = 7.2 nm is the “diameter” of the proteinwhich is equivalent to twice the Stokes radius,49 NA = 6.023 × 1023mol^-1 is the Avogadro number, and c* = 0.23 g L^-1 (3.3 μM) is the critical bulk supersaturation concentration.

Wetting/Solid Surface

The droplet on the left has a contact angle between 90 and 180 degrees making the strength of the interaction between the solid and the liquid weak. The droplet on the right has a contact angle between 0 and 90 degrees making the strength of the interaction between the solid and the liquid strong.

Wetting is due to two parameters, surface roughness and surface fraction.^[9] By increasing wetting, implants can decrease osseointegration periods by cells more readily binding onto the implant's surface. ^[1] Methods used to increase wetting on titanium are processing parameters such as temperature, time, and pressure (shown in table below). Titanium with stable oxide layers predominantly consisting of TiO2 result in improved wetting of the implant in contact with physiological fluid. ^[10]

Surface	Wetting Angle (degrees)	Pressure (mbar) During Processing	Temperature (degrees C) During Processing	Other Surface Processing
Bare Ti	~50^[8]	-	-	None
TiO₂ TiO Ti₄O₇ TiO₄ (Planar)	~33^[8]	2.2	700	Oxidation
TiO₂ TiO Ti₄O₇ (Planar)	~45^[8]	4	700	Oxidation
TiO₂ TiO Ti₄O₇ TiO₄ (Hollow)	~32^[8]	2.2	400	Oxidation
TiO₂ TiO Ti₄O₇ (Hollow)	~25^[8]	2.6	500	Oxidation
TiO₂ TiO Ti₄O₇ (Hollow)	~8^[8]	4	400	Oxidation
TiO₂ TiO Ti₄O₇ (Hollow)	~20^[8]	4	500	Oxidation
Ti with roughened surface	79.5 ± 4.6^[11]	-	-	Machined Surface
Ti with alkali-treated surface	27.2 ± 6.9^[11]	-	-	Bio-surface

Adsorption

Corrosion

Mechanical abrasion of the titanium oxide film leads to increased corrosion rates. ^[12] Titanium and its alloys are not immune to corrosion when in the human body. Titanium alloys are susceptible to hydrogen adsorption which can induce precipitation of hydrides and eventually lead to brittle failure. ^[12] "Hydrogen embrittlement was observed as an in vivo mechanism of degradation under fretting-crevice corrosion conditions resulting in TiH formation, surface reaction and cracking inside Ti/Ti modular body tapers." ^[12]

Adhesion

The cells at the implant interface are very sensitive to foreign objects. When implants are implanted into the body the cells will begin an inflammatory response and could lead to encapsulation, which will impair function of implanted device. ^[13] The desired cell response of a bioactive surface is biomaterial stabilization, reduction of bacterial-surface infection sites, and biomaterial integration. One example of biomaterial integration is a titanium implant with a engineered biointerface covered with biomimetic motifs. Surfaces with these biomimetic motifs have shown to enhance integrin binding and signaling and stem cell differentiation. Increasing the density of ligand clustering also increased integrin binding. A coating consisting of trimers and pentamers increased the bone-implant contact area by 75% when compared to the current clinical standard of uncoated titanium. ^[14] This increase in area allows for increased cellular integration, and reduces rejection of implanted device. The Langmuir isotherm:
$\Gamma ={B_{\text{ADS}}\Gamma _{\text{max}} \over (1+B_{\text{ADSc}})}$ ,^[8]
where c is the concentration of the adsorbate $\Gamma$ is the max amount of adsorbed protein, B_ADS is the affinity of the adsorbate molecules toward adsorption sites. The Langmuir isotherm can be linearized by rearranging the equation to,
${c \over \Gamma }={{1 \over {B_{\text{ADS}}\Gamma _{\text{max}}}}+{c \over \Gamma _{\text{max}}}}$ ^[8]
This simulation is a good approximation of adsorption to a surface when compared to experimental values. ^[8] The Langmuir isotherm for adsorption of elements onto the titanium surface can be determined by plotting the know parameters. An experiment of fibrinogen adsorption on a titanium surface "confirmed the applicability of the Langmuir isotherm in the description of adsorption of fibrinogen onto Ti surface." ^[8]

References

^ ^a ^b Raines, Andrew; et al. "Regulation of angiogenesis during osseointegration by titanium surface microstructure and energy". Biomaterials. Retrieved 23 May 2012. {{cite web}}: Explicit use of et al. in: |last= (help)
^ "Medical Data Sheet" (PDF). International Titanium Association. Retrieved 23 May 2012.
^ ^a ^b "Standard Reduction Potentials (25oC)".
^ ^a ^b Brown, Doc. "Chemistry of Titanium".
^ ^a ^b Winter, Mark. "Titanium compounds".
^ ^a ^b Healy, Ducheyne. "A physical model for titanium-tissue interface". Retrieved 23 May 2012.
^ Long, Rack. "Titanium alloys in total joint replacement". Biomaterials. Retrieved 23 May 2012.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Jackson, Douglas R., Sasha Omanovic, and Sharon G. Roscoe. "Electrochemical Studies of the Adsorption Behavior of Serum Proteins on Titanium". ACS Publications. Retrieved 23 May 2012.{{cite web}}: CS1 maint: multiple names: authors list (link)
^ Bico, Thiele, Quere, Jose, Uwn, David. "Wetting of textured surfaces". Elsevier. Retrieved 23 May 2012.{{cite web}}: CS1 maint: multiple names: authors list (link)
^ M.A.M. Silva; et al. "Surface modification of Ti implants by plasma oxidation in hollow cathode discharge". Elsevier. Retrieved 24 May 2012. {{cite web}}: Explicit use of et al. in: |last= (help)
^ ^a ^b Strnad, Jakub; et al. "Bio-activated titanium surface utilizable for mimetic bone implantation in dentistry—Part III: Surface characteristics and bone–implant contact formation" (PDF). Elsevier. Retrieved 26 May 2012. {{cite web}}: Explicit use of et al. in: |last= (help)
^ ^a ^b ^c Rodrigues, Urban, Jacobs, Gilbert. "In vivo severe corrosion and hydrogen embrittlement of retrieved modular body titanium alloy hip-implants". J Biomed Mater Res B Appl Biomater. Retrieved 23 May 2012.{{cite web}}: CS1 maint: multiple names: authors list (link)
^ Franz, Sandra; et al. "Immune responses to implants". Biomaterials. Retrieved 23 May 2012. {{cite web}}: Explicit use of et al. in: |last= (help)
^ Petrie, Timothy; et al. "Biomaterial Integration Multivalent Integrin-Specific Ligands Enhance Tissue Healing and Biomaterial Integration" (PDF). Sci Transl Med. Retrieved 23 May 2012. {{cite web}}: Explicit use of et al. in: |last= (help)

[raines-1] Raines, Andrew; et al. "Regulation of angiogenesis during osseointegration by titanium surface microstructure and energy". Biomaterials. Retrieved 23 May 2012. {{cite web}}: Explicit use of et al. in: |last= (help)

[2] "Medical Data Sheet" (PDF). International Titanium Association. Retrieved 23 May 2012.

[poten-3] "Standard Reduction Potentials (25oC)".

[compounds2-4] Brown, Doc. "Chemistry of Titanium".

[compounds-5] Winter, Mark. "Titanium compounds".

[healy-6] Healy, Ducheyne. "A physical model for titanium-tissue interface". Retrieved 23 May 2012.

[7] Long, Rack. "Titanium alloys in total joint replacement". Biomaterials. Retrieved 23 May 2012.

[jackson-8] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Jackson, Douglas R., Sasha Omanovic, and Sharon G. Roscoe. "Electrochemical Studies of the Adsorption Behavior of Serum Proteins on Titanium". ACS Publications. Retrieved 23 May 2012.{{cite web}}: CS1 maint: multiple names: authors list (link)

[9] Bico, Thiele, Quere, Jose, Uwn, David. "Wetting of textured surfaces". Elsevier. Retrieved 23 May 2012.{{cite web}}: CS1 maint: multiple names: authors list (link)

[10] M.A.M. Silva; et al. "Surface modification of Ti implants by plasma oxidation in hollow cathode discharge". Elsevier. Retrieved 24 May 2012. {{cite web}}: Explicit use of et al. in: |last= (help)

[Bio-11] Strnad, Jakub; et al. "Bio-activated titanium surface utilizable for mimetic bone implantation in dentistry—Part III: Surface characteristics and bone–implant contact formation" (PDF). Elsevier. Retrieved 26 May 2012. {{cite web}}: Explicit use of et al. in: |last= (help)

[urban-12] Rodrigues, Urban, Jacobs, Gilbert. "In vivo severe corrosion and hydrogen embrittlement of retrieved modular body titanium alloy hip-implants". J Biomed Mater Res B Appl Biomater. Retrieved 23 May 2012.{{cite web}}: CS1 maint: multiple names: authors list (link)

[13] Franz, Sandra; et al. "Immune responses to implants". Biomaterials. Retrieved 23 May 2012. {{cite web}}: Explicit use of et al. in: |last= (help)

[14] Petrie, Timothy; et al. "Biomaterial Integration Multivalent Integrin-Specific Ligands Enhance Tissue Healing and Biomaterial Integration" (PDF). Sci Transl Med. Retrieved 23 May 2012. {{cite web}}: Explicit use of et al. in: |last= (help)

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