Titanium biocompatibility

Last updated April 24, 2024

Titanium dental implants Teeth.jpg — Titanium dental implants

Titanium was first introduced into surgeries in the 1950s after having been used in dentistry for a decade prior.^[1] It is now the metal of choice for prosthetics, internal fixation, inner body devices, and instrumentation. Titanium is 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 affect biocompatibility are surface texture, steric hindrance, binding sites, and hydrophobicity (wetting). These characteristics are optimized to create an ideal cellular response. Some medical implants, as well as parts of surgical instruments are coated with titanium nitride (TiN).

Biocompatibility

Titanium is considered the most biocompatible metal due to its resistance to corrosion from bodily fluids, bio-inertness, capacity for osseointegration, and high fatigue limit. Titanium's ability to withstand the harsh bodily environment is a result of the protective oxide film that forms naturally in the presence of oxygen. The oxide film is strongly adhered, insoluble, and chemically impermeable, preventing reactions between the metal and the surrounding environment.^{[ citation needed ]}

Osseointegration interaction and proliferation

High energy surfaces induce angiogenesis during osseointegration

It has been suggested that titanium's capacity for osseointegration stems from the high dielectric constant of its surface oxide, which does not denature proteins (like tantalum, and cobalt alloys).^[2] Its ability to physically bond with bone gives titanium an advantage over other materials that require the use of an adhesive to remain attached. Titanium implants last longer and much higher forces are required to break the bonds that join them to the body compared to their alternatives.^[3]

Surface properties determine osseointegration

The surface properties of a biomaterial play an important role in determining cellular response (cell adhesion and proliferation) to the material. Titanium's microstructure and high surface energy enable it to induce angiogenesis, which assists in the process of osseointegration.^[4]

Surface energy

Redox potential

Titanium can have many different standard electrode potentials depending on its oxidation state. Solid titanium has a standard electrode potential of -1.63V. Materials with a greater standard electrode potential are more easily reduced, making them better oxidizing agents.^[5] As can be seen in the table below, solid titanium prefers to undergo oxidation, making it a better reducing agent.

Half reaction	Standard electrode potential (V)
Ti²⁺ + 2 e⁻ → Ti(s)	-1.63^[5]
Ti³⁺ + 3 e⁻ → Ti(s)	-1.21^[6]
TiO₂⁺ + 2 H⁺ + 4 e⁻ → Ti(s) + H₂O	-0.86^[7]
2 TiO₂(s) + 2 H⁺ + 2 e⁻ → Ti₂O₃(s) + H₂O	-0.56^[7]
Ti²⁺(aq)/M³⁺(aq)	-0.36^[6]

Surface coating

Titanium naturally passivates, forming an oxide film that becomes heterogeneous and polarized as a function of exposure time to bodily environments.^[8] This leads to the increased adsorption of hydroxyl groups, lipoproteins, and glycolipids over time.^[8] The adsorption of these compounds changes how the material interacts with the body and can improve biocompatibility. In titanium alloys such as Ti-Zr and Ti-Nb, zirconium and niobium ions that are liberated due to corrosion are not released into the patient's body, but rather added to the passivation layer.^[9] The alloying elements in the passive layer add a degree of biocompatibility and corrosion resistance depending on the original alloy composition of the bulk metal prior to corrosion.

Protein surface concentration, ( $\Gamma$ ), is defined by the equation

$\Gamma ={Q_{\text{ADS}}M \over nF}$ ^[10]

where Q_ADS is the surface charge density in C⋅cm⁻², M 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.

The equation for collision frequency is as follows:

$v_{\text{c}}={2\pi DcdN_{\text{A}}}$ ^[10]

where D = 8.83 × 10⁻⁷ cm²⋅s⁻¹ is the diffusion coefficient of the BSA molecule at 310 K, d = 7.2 nm is the "diameter" of the proteinwhich is equivalent to twice the Stokes radius, N_A = 6.023 × 10²³ mol⁻¹ is the Avogadro constant, and c* = 0.23 g⋅L⁻¹ (3.3 μM) is the critical bulk supersaturation concentration.

Wetting and solid surface

The droplet on the left has a contact angle between 90 and 180 degrees, rendering the interaction between the solid and the liquid relatively weak. In contrast, the droplet on the right has a contact angle between 0 and 90 degrees making the interaction between the solid and the liquid strong. Wetting.jpg — The droplet on the left has a contact angle between 90 and 180 degrees, rendering the interaction between the solid and the liquid relatively weak. In contrast, the droplet on the right has a contact angle between 0 and 90 degrees making the interaction between the solid and the liquid strong.

Wetting occurs as a function of two parameters: surface roughness and surface fraction.^[11] By increasing wetting, implants can decrease the time required for osseointegration by allowing cells to more readily bind to the surface of an implant.^[3] Wetting of titanium can be modified by optimizing process 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.^[12]

Surface	Wetting angle (degrees)	Pressure (mbar) during processing	Temperature (degrees C) during processing	Other surface processing
Bare Ti	~50^[10]	-	-	None
TiO₂ TiO Ti₄O₇ TiO₄ (Planar)	~33^[12]	2.2	700	Oxidation
TiO₂ TiO Ti₄O₇ (Planar)	~45^[12]	4	700	Oxidation
TiO₂ TiO Ti₄O₇ TiO₄ (Hollow)	~32^[12]	2.2	400	Oxidation
TiO₂ TiO Ti₄O₇ (Hollow)	~25^[12]	2.6	500	Oxidation
TiO₂ TiO Ti₄O₇ (Hollow)	~8^[12]	4	400	Oxidation
TiO₂ TiO Ti₄O₇ (Hollow)	~20^[12]	4	500	Oxidation
Ti with roughened surface	79.5 ± 4.6^[13]	-	-	Machined surface
Ti with alkali-treated surface	27.2 ± 6.9^[13]	-	-	Bio-surface

Adsorption

Corrosion

Mechanical abrasion of the titanium oxide film leads to an increased rate of corrosion.^[14]

Titanium and its alloys are not immune to corrosion when in the human body. Titanium alloys are susceptible to hydrogen absorption which can induce precipitation of hydrides and cause embrittlement, leading to material failure.^[14] "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."^[14] Studying and testing titanium behavior in the body allow us to avoid malpractices that would cause a fatal breakdown in the implant, like the usage of dental products with high fluoride concentration or substances capable of lowering the pH of the media around the implant.^[15]

Adhesion

The cells at the implant interface are highly sensitive to foreign objects. When implants are installed into the body, the cells initiate an inflammatory response which could lead to encapsulation, impairing the functioning of the implanted device.^[16]

The ideal cell response to a bioactive surface is characterized by biomaterial stabilization and integration, as well as the reduction of potential bacterial infection sites on the surface. One example of biomaterial integration is a titanium implant with an 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.^[17] This increase in area allows for increased cellular integration, and reduces rejection of implanted device. The Langmuir isotherm:

$\Gamma ={B_{\text{ADS}}\Gamma _{\text{max}} \over (1+cB_{\text{ADS}})}$ ,^[10]

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,

${c \over \Gamma }={{1 \over {B_{\text{ADS}}\Gamma _{\text{max}}}}+{c \over \Gamma _{\text{max}}}}$ ^[10]

This simulation is a good approximation of adsorption to a surface when compared to experimental values.^[10] 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."^[10]

Related Research Articles

Titanium is a chemical element; it has symbol Ti and atomic number 22. Found in nature only as an oxide, it can be reduced to produce a lustrous transition metal with a silver color, low density, and high strength, resistant to corrosion in sea water, aqua regia, and chlorine.

A monolayer is a single, closely packed layer of entities, commonly atoms or molecules. Monolayers can also be made out of cells. Self-assembled monolayers form spontaneously on surfaces. Monolayers of layered crystals like graphene and molybdenum disulfide are generally called 2D materials.

Adsorption is the adhesion of atoms, ions or molecules from a gas, liquid or dissolved solid to a surface. This process creates a film of the adsorbate on the surface of the adsorbent. This process differs from absorption, in which a fluid is dissolved by or permeates a liquid or solid. While adsorption does often precede absorption, which involves the transfer of the absorbate into the volume of the absorbent material, alternatively, adsorption is distinctly a surface phenomenon, wherein the adsorbate does not penetrate through the material surface and into the bulk of the adsorbent. The term sorption encompasses both adsorption and absorption, and desorption is the reverse of sorption.

Wetting is the ability of a liquid to maintain contact with a solid surface, resulting from intermolecular interactions when the two are brought together. This happens in presence of a gaseous phase or another liquid phase not miscible with the first one. The degree of wetting (wettability) is determined by a force balance between adhesive and cohesive forces. There are two types of wetting: non-reactive wetting and reactive wetting.

An implant is a medical device manufactured to replace a missing biological structure, support a damaged biological structure, or enhance an existing biological structure. For example, an implant may be a rod, used to strengthen weak bones. Medical implants are human-made devices, in contrast to a transplant, which is a transplanted biomedical tissue. The surface of implants that contact the body might be made of a biomedical material such as titanium, silicone, or apatite depending on what is the most functional. In 2018, for example, American Elements developed a nickel alloy powder for 3D printing robust, long-lasting, and biocompatible medical implants. In some cases implants contain electronics, e.g. artificial pacemaker and cochlear implants. Some implants are bioactive, such as subcutaneous drug delivery devices in the form of implantable pills or drug-eluting stents.

Titanium aluminide, commonly gamma titanium, is an intermetallic chemical compound. It is lightweight and resistant to oxidation and heat, but has low ductility. The density of γ-TiAl is about 4.0 g/cm³. It finds use in several applications including aircraft, jet engines, sporting equipment and automobiles. The development of TiAl based alloys began circa 1970. The alloys have been used in these applications only since about 2000.

A foreign body reaction (FBR) is a typical tissue response to a foreign body within biological tissue. It usually includes the formation of a foreign body granuloma. Tissue-encapsulation of an implant is an example, as is inflammation around a splinter. Foreign body granuloma formation consists of protein adsorption, macrophages, multinucleated foreign body giant cells, fibroblasts, and angiogenesis. It has also been proposed that the mechanical property of the interface between an implant and its surrounding tissues is critical for the host response.

Nitinol biocompatibility is an important factor in biomedical applications. Nitinol (NiTi), which is formed by alloying nickel and titanium, is a shape-memory alloy with superelastic properties more similar to that of bone, when compared to stainless steel, another commonly used biomaterial. Biomedical applications that utilize nitinol include stents, heart valve tools, bone anchors, staples, septal defect devices and implants. It is a commonly used biomaterial especially in the development of stent technology.

Bioceramics and bioglasses are ceramic materials that are biocompatible. Bioceramics are an important subset of biomaterials. Bioceramics range in biocompatibility from the ceramic oxides, which are inert in the body, to the other extreme of resorbable materials, which are eventually replaced by the body after they have assisted repair. Bioceramics are used in many types of medical procedures. Bioceramics are typically used as rigid materials in surgical implants, though some bioceramics are flexible. The ceramic materials used are not the same as porcelain type ceramic materials. Rather, bioceramics are closely related to either the body's own materials or are extremely durable metal oxides.

Adsorption is the accumulation and adhesion of molecules, atoms, ions, or larger particles to a surface, but without surface penetration occurring. The adsorption of larger biomolecules such as proteins is of high physiological relevance, and as such they adsorb with different mechanisms than their molecular or atomic analogs. Some of the major driving forces behind protein adsorption include: surface energy, intermolecular forces, hydrophobicity, and ionic or electrostatic interaction. By knowing how these factors affect protein adsorption, they can then be manipulated by machining, alloying, and other engineering techniques to select for the most optimal performance in biomedical or physiological applications.

Adsorption is the adhesion of ions or molecules onto the surface of another phase. Adsorption may occur via physisorption and chemisorption. Ions and molecules can adsorb to many types of surfaces including polymer surfaces. A polymer is a large molecule composed of repeating subunits bound together by covalent bonds. In dilute solution, polymers form globule structures. When a polymer adsorbs to a surface that it interacts favorably with, the globule is essentially squashed, and the polymer has a pancake structure.

Biomaterials are materials that are used in contact with biological systems. Biocompatibility and applicability of surface modification with current uses of metallic, polymeric and ceramic biomaterials allow alteration of properties to enhance performance in a biological environment while retaining bulk properties of the desired device.

Protein adsorption refers to the adhesion of proteins to solid surfaces. This phenomenon is an important issue in the food processing industry, particularly in milk processing and wine and beer making. Excessive adsorption, or protein fouling, can lead to health and sanitation issues, as the adsorbed protein is very difficult to clean and can harbor bacteria, as is the case in biofilms. Product quality can be adversely affected if the adsorbed material interferes with processing steps, like pasteurization. However, in some cases protein adsorption is used to improve food quality, as is the case in fining of wines.

The strength of metal oxide adhesion effectively determines the wetting of the metal-oxide interface. The strength of this adhesion is important, for instance, in production of light bulbs and fiber-matrix composites that depend on the optimization of wetting to create metal-ceramic interfaces. The strength of adhesion also determines the extent of dispersion on catalytically active metal. Metal oxide adhesion is important for applications such as complementary metal oxide semiconductor devices. These devices make possible the high packing densities of modern integrated circuits.

Ti-6Al-4V, also sometimes called TC4, Ti64, or ASTM Grade 5, is an alpha-beta titanium alloy with a high specific strength and excellent corrosion resistance. It is one of the most commonly used titanium alloys and is applied in a wide range of applications where low density and excellent corrosion resistance are necessary such as e.g. aerospace industry and biomechanical applications.

Biomaterials exhibit various degrees of compatibility with the harsh environment within a living organism. They need to be nonreactive chemically and physically with the body, as well as integrate when deposited into tissue. The extent of compatibility varies based on the application and material required. Often modifications to the surface of a biomaterial system are required to maximize performance. The surface can be modified in many ways, including plasma modification and applying coatings to the substrate. Surface modifications can be used to affect surface energy, adhesion, biocompatibility, chemical inertness, lubricity, sterility, asepsis, thrombogenicity, susceptibility to corrosion, degradation, and hydrophilicity.

Ultra-low fouling is a rating of a surface's ability to shed potential contamination. Surfaces are prone to contamination, which is a phenomenon known as fouling. Unwanted adsorbates caused by fouling change the properties of a surface, which is often counter-productive to the function of that surface. Consequently, a necessity for anti-fouling surfaces has arisen in many fields: blocked pipes inhibit factory productivity, biofouling increases fuel consumption on ships, medical devices must be kept sanitary, etc. Although chemical fouling inhibitors, metallic coatings, and cleaning processes can be used to reduce fouling, non-toxic surfaces with anti-fouling properties are ideal for fouling prevention. To be considered effective, an ultra-low fouling surface must be able to repel and withstand the accumulation of detrimental aggregates down to less than 5 ng/cm². A recent surge of research has been conducted to create these surfaces in order to benefit the biological, nautical, mechanical, and medical fields.

As with any material implanted in the body, it is important to minimize or eliminate foreign body response and maximize effectual integration. Neural implants have the potential to increase the quality of life for patients with such disabilities as Alzheimer's, Parkinson's, epilepsy, depression, and migraines. With the complexity of interfaces between a neural implant and brain tissue, adverse reactions such as fibrous tissue encapsulation that hinder the functionality, occur. Surface modifications to these implants can help improve the tissue-implant interface, increasing the lifetime and effectiveness of the implant.

Ti-6Al-7Nb is an alpha-beta titanium alloy first synthesized in 1977 containing 6% aluminum and 7% niobium. It features high strength and has similar properties as the cytotoxic vanadium containing alloy Ti-6Al-4V. Ti-6Al-7Nb is used as a material for hip prostheses.

Titanium foams exhibit high specific strength, high energy absorption, excellent corrosion resistance and biocompatibility. These materials are ideally suited for applications within the aerospace industry. An inherent resistance to corrosion allows the foam to be a desirable candidate for various filtering applications. Further, titanium's physiological inertness makes its porous form a promising candidate for biomedical implantation devices. The largest advantage in fabricating titanium foams is that the mechanical and functional properties can be adjusted through manufacturing manipulations that vary porosity and cell morphology. The high appeal of titanium foams is directly correlated to a multi-industry demand for advancement in this technology.

References

↑ Fischer J (December 2000). "Mechanical, thermal, and chemical analyses of the binary system Au-Ti in the development of a dental alloy". J. Biomed. Mater. Res. 52 (4): 678–86. doi:10.1002/1097-4636(20001215)52:4<678::AID-JBM12>3.0.CO;2-P. PMID 11033550.
↑ Black, Jonathan (January 1994). "Biologic performance of tantalum". Clinical Materials. 16 (3): 167–173. doi:10.1016/0267-6605(94)90113-9.
1 2 Raines, Andrew L.; Olivares-Navarrete, Rene; Wieland, Marco; Cochran, David L.; Schwartz, Zvi; Boyan, Barbara D. (2010). "Regulation of angiogenesis during osseointegration by titanium surface microstructure and energy". Biomaterials. 31 (18): 4909–17. doi:10.1016/j.biomaterials.2010.02.071. PMC 2896824 . PMID 20356623.
↑ http://titaniumthemetal.org/Resources/DataSheetMedical.pdf ^{[ bare URL PDF ]}
1 2 "Standard Reduction Potentials (25oC)". Archived from the original on 2013-06-18. Retrieved 2012-10-23.
1 2 Brown, Doc. "Chemistry of Titanium".
1 2 Winter, Mark. "Titanium compounds".
1 2 Healy, Kevin E.; Ducheyne, Paul (1991). "A physical model for the titanium-tissue interface". ASAIO Transactions. 37 (3): M150–1. PMID 1751087.
↑ Long, Marc; Rack, H.J (1998). "Titanium alloys in total joint replacement—a materials science perspective". Biomaterials. 19 (18): 1621–39. doi:10.1016/S0142-9612(97)00146-4. PMID 9839998.
1 2 3 4 5 6 7 Jackson, Douglas R.; Omanović, Saša; Roscoe, Sharon G. (2000). "Electrochemical Studies of the Adsorption Behavior of Serum Proteins on Titanium". Langmuir. 16 (12): 5449–57. doi:10.1021/la991497x.
↑ Bico, José; Thiele, Uwe; Quéré, David (2002). "Wetting of textured surfaces". Colloids and Surfaces A: Physicochemical and Engineering Aspects. 206 (1–3): 41–6. doi:10.1016/S0927-7757(02)00061-4.
1 2 3 4 5 6 7 Silva, M.A.M.; Martinelli, A.E.; Alves, C.; Nascimento, R.M.; Távora, M.P.; Vilar, C.D. (2006). "Surface modification of Ti implants by plasma oxidation in hollow cathode discharge". Surface and Coatings Technology. 200 (8): 2618–26. doi:10.1016/j.surfcoat.2004.12.027.
1 2 Strnad, Jakub; Strnad, Zdeněk; Šesták, Jaroslav; Urban, Karel; Povýšil, Ctibor (2007). "Bio-activated titanium surface utilizable for mimetic bone implantation in dentistry—Part III: Surface characteristics and bone–implant contact formation". Journal of Physics and Chemistry of Solids. 68 (5–6): 841–5. Bibcode:2007JPCS...68..841S. doi:10.1016/j.jpcs.2007.02.040.
1 2 3 Rodrigues, Danieli C.; Urban, Robert M.; Jacobs, Joshua J.; Gilbert, Jeremy L. (2009). "In vivo severe corrosion and hydrogen embrittlement of retrieved modular body titanium alloy hip-implants". Journal of Biomedical Materials Research Part B: Applied Biomaterials. 88 (1): 206–19. doi:10.1002/jbm.b.31171. PMC 2667129 . PMID 18683224.
↑ "Archived copy" (PDF). Archived from the original (PDF) on 2016-03-04. Retrieved 2015-06-01.{{cite web}}: CS1 maint: archived copy as title (link)
↑ Franz, Sandra; Rammelt, Stefan; Scharnweber, Dieter; Simon, Jan C. (2011). "Immune responses to implants – A review of the implications for the design of immunomodulatory biomaterials". Biomaterials. 32 (28): 6692–709. doi:10.1016/j.biomaterials.2011.05.078. PMID 21715002.
↑ Petrie, T. A.; Raynor, J. E.; Dumbauld, D. W.; Lee, T. T.; Jagtap, S.; Templeman, K. L.; Collard, D. M.; Garcia, A. J. (2010). "Multivalent Integrin-Specific Ligands Enhance Tissue Healing and Biomaterial Integration". Science Translational Medicine. 2 (45): 45ra60. doi:10.1126/scitranslmed.3001002. PMC 3128787 . PMID 20720217.

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[1] Fischer J (December 2000). "Mechanical, thermal, and chemical analyses of the binary system Au-Ti in the development of a dental alloy". J. Biomed. Mater. Res. 52 (4): 678–86. doi:10.1002/1097-4636(20001215)52:4<678::AID-JBM12>3.0.CO;2-P. PMID 11033550.

[Black-2] Black, Jonathan (January 1994). "Biologic performance of tantalum". Clinical Materials. 16 (3): 167–173. doi:10.1016/0267-6605(94)90113-9.

[raines-3] 1 2 Raines, Andrew L.; Olivares-Navarrete, Rene; Wieland, Marco; Cochran, David L.; Schwartz, Zvi; Boyan, Barbara D. (2010). "Regulation of angiogenesis during osseointegration by titanium surface microstructure and energy". Biomaterials. 31 (18): 4909–17. doi:10.1016/j.biomaterials.2010.02.071. PMC 2896824 . PMID 20356623.

[4] ttp://titaniumthemetal.org/Resources/DataSheetMedical.pdf ^{[ bare URL PDF ]}

[poten-5] 1 2 "Standard Reduction Potentials (25oC)". Archived from the original on 2013-06-18. Retrieved 2012-10-23.

[compounds2-6] 1 2 Brown, Doc. "Chemistry of Titanium".

[compounds-7] 1 2 Winter, Mark. "Titanium compounds".

[healy-8] 1 2 Healy, Kevin E.; Ducheyne, Paul (1991). "A physical model for the titanium-tissue interface". ASAIO Transactions. 37 (3): M150–1. PMID 1751087.

[9] Long, Marc; Rack, H.J (1998). "Titanium alloys in total joint replacement—a materials science perspective". Biomaterials. 19 (18): 1621–39. doi:10.1016/S0142-9612(97)00146-4. PMID 9839998.

[jackson-10] 1 2 3 4 5 6 7 Jackson, Douglas R.; Omanović, Saša; Roscoe, Sharon G. (2000). "Electrochemical Studies of the Adsorption Behavior of Serum Proteins on Titanium". Langmuir. 16 (12): 5449–57. doi:10.1021/la991497x.

[11] Bico, José; Thiele, Uwe; Quéré, David (2002). "Wetting of textured surfaces". Colloids and Surfaces A: Physicochemical and Engineering Aspects. 206 (1–3): 41–6. doi:10.1016/S0927-7757(02)00061-4.

[silva06-12] 1 2 3 4 5 6 7 Silva, M.A.M.; Martinelli, A.E.; Alves, C.; Nascimento, R.M.; Távora, M.P.; Vilar, C.D. (2006). "Surface modification of Ti implants by plasma oxidation in hollow cathode discharge". Surface and Coatings Technology. 200 (8): 2618–26. doi:10.1016/j.surfcoat.2004.12.027.

[Bio-13] 1 2 Strnad, Jakub; Strnad, Zdeněk; Šesták, Jaroslav; Urban, Karel; Povýšil, Ctibor (2007). "Bio-activated titanium surface utilizable for mimetic bone implantation in dentistry—Part III: Surface characteristics and bone–implant contact formation". Journal of Physics and Chemistry of Solids. 68 (5–6): 841–5. Bibcode:2007JPCS...68..841S. doi:10.1016/j.jpcs.2007.02.040.

[urban-14] 1 2 3 Rodrigues, Danieli C.; Urban, Robert M.; Jacobs, Joshua J.; Gilbert, Jeremy L. (2009). "In vivo severe corrosion and hydrogen embrittlement of retrieved modular body titanium alloy hip-implants". Journal of Biomedical Materials Research Part B: Applied Biomaterials. 88 (1): 206–19. doi:10.1002/jbm.b.31171. PMC 2667129 . PMID 18683224.

[15] "Archived copy" (PDF). Archived from the original (PDF) on 2016-03-04. Retrieved 2015-06-01.{{cite web}}: CS1 maint: archived copy as title (link)

[16] Franz, Sandra; Rammelt, Stefan; Scharnweber, Dieter; Simon, Jan C. (2011). "Immune responses to implants – A review of the implications for the design of immunomodulatory biomaterials". Biomaterials. 32 (28): 6692–709. doi:10.1016/j.biomaterials.2011.05.078. PMID 21715002.

[17] Petrie, T. A.; Raynor, J. E.; Dumbauld, D. W.; Lee, T. T.; Jagtap, S.; Templeman, K. L.; Collard, D. M.; Garcia, A. J. (2010). "Multivalent Integrin-Specific Ligands Enhance Tissue Healing and Biomaterial Integration". Science Translational Medicine. 2 (45): 45ra60. doi:10.1126/scitranslmed.3001002. PMC 3128787 . PMID 20720217.

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