Surface modification strategies to improve titanium hemocompatibility: a comprehensive review

Abstract

Titanium and its alloys are widely used in different biomaterial applications due to their remarkable mechanical properties and bio-inertness. However, titanium-based materials still face some challenges, with an emphasis on hemocompatibility. Blood-contacting devices such as stents, heart valves, and circulatory devices are prone to thrombus formation, restenosis, and inflammation due to inappropriate blood-implant surface interactions. After implantation, when blood encounters these implant surfaces, a series of reactions takes place, such as protein adsorption, platelet adhesion and activation, and white blood cell complex formation as a defense mechanism. Currently, patients are prescribed anticoagulant drugs to prevent blood clotting, but these drugs can weaken their immune system and cause profound bleeding during injury. Extensive research has been done to modify the surface properties of titanium to enhance its hemocompatibility. Results have shown that the modification of surface morphology, roughness, and chemistry has been effective in reducing thrombus formation. The main focus of this review is to analyze and understand the different modification techniques on titanium-based surfaces to enhance hemocompatibility and, consequently, recognize the unresolved challenges and propose scopes for future research.

Fig. 1. (A) Thrombus formation around the heart valve frame and strut. Reproduced with permission from ref. 9. Copyright 2016, Elsevier. Examples of thrombosis in a HeartMate II device. (B) Fibrin formation and (C) fibrin with thrombus formation. Reproduced with permission from ref. 10. Copyright 2014, Elsevier.

Fig. 2. Crystal structure transformation of titanium. Adapted with permission from ref. 28. Copyright 2013, Elsevier.

Fig. 3. Schematic representation of medical device associated thrombosis. The initial protein adsorption on the implant surface mediates all the subsequent phenomena. Reproduced with permission from ref. 5. Copyright 2019, Elsevier.

Fig. 4. Platelet adhesion and activation on the biomaterial surface.

Fig. 5. Different strategies of surface modification on titanium-based surfaces to improve hemocompatibility.

Fig. 6. (A and B) SEM images of red blood cells on control surfaces and plasma oxidized surfaces at 280 W for 30 min, respectively. SEM images showing the interaction of platelets with (C) titanium surfaces and (D) oxygen PIII treated surfaces. Reproduced with permission from ref. 86. Copyright 2016, Elsevier.

Fig. 7. (A) SEM images showing the surface morphology of hydrothermally treated nanograss surfaces. (B and C) SEM images showing platelet adhesion on control and nanograss Ti29Nb alloy surfaces, respectively. Adapted with permission from ref. 90. Copyright 2020, Elsevier. (D) SEM images showing the morphology of control and hydrothermally treated titanium surfaces, respectively. (E and F) SEM images showing platelets and leukocytes adhered on control and hydrothermally treated titanium surfaces, respectively.

Fig. 8. (A) SEM images showing the surface morphology of zinc doped TiO₂ nanotubes. (B and C) SEM images showing platelet adhesion on control and zinc doped TiO₂ nanotubes, respectively. Adapted with permission from ref. 95. Copyright 2020, American Chemical Society. (D) SEM images showing the surface morphology of TiO₂ nanotube arrays anodized at 30 V. (E and F) SEM images showing platelet adhesion on control and TiO₂ nanotube arrays (anodized at 30 V). Adapted with permission from ref. 96. Copyright 2019, Elsevier.

Fig. 9. (A) SEM images showing a crater-like porous microstructure on the Ti–6Al–4V surface. (B and C) SEM images showing platelet adhesion on bare Ti–6Al–4V and superhydrophobic MAO + TFOS surfaces, respectively. Adapted with permission from ref. 101. Copyright 2015, Elsevier. (D) SEM image showing superhydrophobic TiO₂ nanotube surfaces. (E and F) SEM images showing platelet adhesion on a bare TiO₂ nanotube surface and a PTES modified superhydrophobic surface, respectively, after 120 min exposure. Adapted with permission from ref. 103. Copyright 2010, Elsevier. (G) SEM image showing multifunctional 3D micro-nanostructures on the nickel–titanium surface. (H and I) SEM images showing platelet adhesion on the pristine nickel–titanium surface and superhydrophobic multifunctional 3D micro-nanostructured surface. Adapted with permission from ref. 104. Copyright 2020, American Chemical Society. (J) SEM images showing nano-flowered surfaces. (K and L) SEM images showing platelet adhesion on non-textured titanium and superhemophobic nanoflower titanium surfaces. Adapted with permission from ref. 105. Copyright 2016, Wiley-VCH.

Fig. 10. (A) SEM image showing the surface microtopography of a titanium surface modified with PTL/heparin. (B and C) Fluorescence images showing the adhesion of platelets on bare titanium and titanium modified with PTL/heparin, respectively. Adapted with permission from ref. 120. Copyright 2019, Elsevier. (D) SEM images showing the morphology of titanium surfaces modified with heparin/chitosan. (E and F) SEM images showing platelet adhesion on titanium and titanium surfaces modified with heparin/chitosan, respectively. Adapted with permission from ref. 112. Copyright 2018, Elsevier. (G) SEM image showing titania nanotube surfaces modified with tanfloc/heparin polyelectrolyte multilayers. (H and I) SEM images showing platelet adhesion on unmodified titania nanotube surfaces and titania nanotube surfaces modified with tanfloc/heparin, respectively. Adapted with permission from ref. 110. Copyright 2020, Wiley-VCH. (J–L) SEM images showing platelet adhesion on pristine titanium, TA/SS 1, and TA/SS 2 coated surfaces – 1 and 2 indicating different volume ratios. Adapted with permission from ref. 126. Copyright 2020, Elsevier. (M–O) SEM images showing platelet adhesion on non-treated, tannic acid-treated, and ulvan-coated Ti/TiO₂ surfaces, respectively. Adapted with permission from ref. 128. Copyright 2020, Elsevier.

Fig. 11. (A–C) SEM images showing TiO₂NT, TiO₂NT + PEM and TiO₂NT + PEM + NO surfaces. (D–G) SEM images showing adhered cells on bare titanium, TiO₂NT, TiO₂NT + PEM and TiO₂NT + PEM + NO surfaces. Adapted with permission from ref. 135. Copyright 2017, American Chemical Society. (H–J) SEM images showing the surface morphology of HA micro-patterned titanium surfaces modified with EC-ECM (ECM_EC/HAP), SMC-ECM (ECM_SMC/HAP), and both SMC-ECM and EC-ECM (ECM_SMC/EC/HAP), respectively. (K–N) SEM images showing platelet adhesion on respective surfaces. (O–R) Fluorescence images showing the growth of HUVECs after 3 days on respective surfaces.

Fig. 12. (A and B) SEM images showing the surface morphology of rutile TiO₂ nanorod arrays (TNA). (C) SEM images showing the surface morphology of the ZrN film. (D and E) SEM images showing platelet adhesion on nickel–titanium SMA and ZrN film surfaces, respectively. Adapted with permission from ref. 141. Copyright 2010, Elsevier.