On the Immune Regulation of Bone Response to Biomaterials
Abstract
Osseointegration is the biological basis for bone anchorage of oral implants, and revolu-tionized the replacement of lost teeth. It is also applied in bone anchored hearing aids and limb replacement in amputees. In biomaterial science, the in vivo mechanisms involved in host-biomaterial interaction - the foreign body reaction (FBR) – have been studied in soft tissues but not in bone. The present thesis aims to explore these important mechanisms in bone.
A literature review of current knowledge in FBR identified the immune system as central for host tissue response to biomaterials: materials modulate the immune system, which in turn directly regulates the local tissue reaction (Paper I). A hypothesis was developed that titanium, rather than inert, is immunomodulatory in bone and osseointegration the result of a specific immune-inflammatory reaction triggered by titanium, in an attempt to isolate the foreign material from the rest of the body.
In vivo animal pilot studies were performed (rabbit model, in femur and tibia bone), to explore the aforementioned immune mechanisms. The methods used were gene expression analysis to explore the cell and molecular mechanisms, and histology to study the bone tissue response.
The first experimental study (Paper II) compared bone healing around titanium versus normal bone healing without a biomaterial (sham), demonstrating that titanium is not inert, rather induces an immune reaction in bone up to at least 28 days.
A second experimental study (Paper III) compared materials titanium (osseointegrating material), copper and PEEK (non osseointegrating) versus sham (natural bone healing) at 10 days, demonstrating that titanium suppresses pro-inflammatory (M1-macrophage) and promotes a reparative reaction (M2-macrophage), whereas the other materials maintain a mixed M1/M2 reaction, i.e. still a pro-inflammatory environment at an early healing stage. These results suggest that osseointegration is defined at an early stage in biomaterial heal-ing; also, that PEEK is not inert.
A final experimental study (Paper IV) compared the 10 days results in Paper III with 28 days (post-inflammatory period) on a copper and PEEK with titanium as a control study; the results showed a continued activation of M1 and M2 around copper and PEEK at 28 days, and also that PEEK may have a specific mechanism that induces adipose tissue for-mation instead of bone.
In conclusion, bone reaction is specific to the type of implanted material, titanium is im-munogenic and osseointegration the result of a specific immune-inflammatory balance triggered by titanium in bone.
Parts of work
I. Trindade R, Albrektsson T, Tengvall P, Wennerberg A. Foreign body reaction to biomaterials: On mechanisms for buildup and breakdown of osseointegration. Clin Implant Dent Relat Res 2016; 18(1):192-203. ::doi::10.1111/cid.12274 II. Trindade R, Albrektsson T, Galli S, Prgomet Z, Tengvall P, Wennerberg A. (2018). Osseointegration and foreign body reaction: Titanium implants activate the immune system and suppress bone resorption during the first 4 weeks after implantation. Clin Implant Dent Relat Res 2018: 20(1):82-91. ::doi::10.1111/cid.12578 III. Trindade R, Albrektsson T, Galli S, Prgomet Z, Tengvall P, Wennerberg A. Bone Immune Response to Materials, Part I: Titanium, PEEK and Copper in Comparison to Sham at 10 Days in Rabbit Tibia. J Clin Med 2018; 7(12):526. ::Doi::10.3390/jcm7120526 IV. Trindade R, Albrektsson T, Galli S, Prgomet Z, Tengvall P, Wennerberg A. Bone Immune Response to Materials, Part II: Copper and Polyetheretherketone (PEEK) Compared to Titanium at 10 and 28 Days in Rabbit Tibia. J Clin Med 2019; 8(6):814. ::doi::10.3390/jcm8060814
Degree
Doctor of Philosophy (Odontology)
University
University of Gothenburg. Sahlgrenska Academy
Institution
Institute of Odontology. Department of Prosthetic Dentistry/Dental Material Science
Disputation
Fredag den 15 november 2019, kl 13.00, Föreläsningssal 3, Medicinaregatan 12, Göteborg
Date of defence
2019-11-15
ricardo.bretes.trindade@gu.se
Date
2019-10-25Author
Trindade, Ricardo
Keywords
Biomaterial
Immune System
Osseointegration
Foreign body reaction
Immune modulation
Titanium
Copper
Polyether ether ketone
PEEK
Publication type
Doctoral thesis
ISBN
978-91-7833-658-6 (Print)
978-91-7833-659-3 (PDF)
Language
eng