The future of Bone Grafting

Author: Dr. Bruno Alves Paim

The filling of bone defects with biomaterials is an increasingly popular practice in dental offices. Currently, by using bone substitutes, the dentist is able to achieve excellent results within the desired timing. The grafting process depends on a few factors that guarantee the conditions for the osteoblasts to proliferate and lead to the formation of new tissue, promoting the conversion of the graft into bone, in a process called osseointegration. In the bone grafting process, the main priorities of a biomaterial are osteogenesis, osteoinduction and osteoconduction. Those concepts might be defined in a very simple way:

1 – Osteogenesis implies the presence of osteoblasts in the biomaterial, which is capable of promoting the synthesis of the new bone tissue right after the surgery;

2 – Osteoinduction is the capacity of recruiting new bone-tissue-forming cells for the site of the graft;

3 – Osteoconduction is related to the capacity of promoting adhesion, survival and proliferation of bone cells, promoting an interconnected structure for the sedimentation of the new bone tissue as well as for the formation of new blood vessels.

Considered gold standard in grafting procedures, the autogenous bone is the only material to unite all those properties. However, that procedure is associated with several inconveniences such as longer recovery time for the patient, post-operative pain, blood loss, damage to nerves adjacent to the bone collection site, infection, to mention a few that are a consensus among professionals. In that scenario, the use of synthetic biomaterials appears as an alternative to autogenous bone. Those synthetic biomaterials are mostly composed of hydroxyapatite-based ceramics (HA) and β-tricalcium phosphate (β-TCP). Both HA and β-TCP are highly biocompatible. HA has a longer degradation time, remaining in the place of implementation for a longer period than the β-TCP. Like all synthetic ceramics, alone, those materials do not have osteogenic or osteoinductive properties. Therefore, the efficacy of those materials depends heavily on how osteoconductive they are.

Analyzing in greater depth the organization of the bone tissue, it is noticeable that the bone is a nanohybrid tissue composed of nanocrystals of HA and nanofibers of collagen, which assume a highly porous structure, with several interconnected pores. Since the bone is naturally nanostructured, synthetic materials with nanometric structures are considered the best choice for grafting procedures. The advantage of that type of material lies in the similarity with the size of the particles of HA, high porosity and large surface area. The HA crystals in nanometric scale, increase the adhesion of the osteoblasts, elevating the proliferation and the adhesion strength between those cells and the biomaterial1. Similar to cellular adhesion, the proliferation and deposition of calcium are significantly greater in HA ceramics with nanometric surfaces when compared to traditional micrometric ceramics currently available in the market1,2. That fact is probably related to the larger surface area of nanoceramics, which allows for a greater deposition of proteins related to the cellular adhesion process.

Besides the size of the HA crystals, the size of the HA granules also interferes with the production of several proteins related to the cell signaling process, called cytokines 3,4,  related to the cellular signaling process. Those cytokines are small proteins produced by several cells with the capacity to modulate the formation of bone tissue. Cytokines such as Interleukin 6 (IL-6) and the alpha tumoral necrosis factor (TTNF- α) are related to the activation of osteoclasts (bone cells related to bone tissue reabsorption). Another cytokine, IL-187, acts the opposite way. That cytokine produced by cells of the immune system and by osteoblasts, is capable of directly inhibiting the activation of osteoclasts by elevating the production of GM-CSF5,6,7. It has been demonstrated in studies that the HA spherical granules with sizes between 150 and 300µm can also lead cells of the immune system to produce smaller amounts of IL-6 and TNF-α when compared to the control group3. When decreasing the size of the HA granule, the levels of those cytokines tend to increase, which could lead to a greater amount of osteoclasts and consequent reduction of formed bone. Similar to what is observed for Cytokines IL-6 and TNF-α, spherical HA particles with sizes between 150 and 300 µm can also stimulate the production of IL-18, which leads to a lower quantity of osteoclasts4. That balance between lower levels of IL-6 and TNF- α, conjugated to an elevation of IL-18 levels can lead to a greater volume of bone tissue formed when HA particles with sizes equal to or greater than 200 µm are used.

Figure 1 – How osteoclasts are activated and regulated. Cytokines such as TNF-α, IL-6 and IFN-γ are related to the process of maturation of osteoclast precursors into osteoclasts. That process is regulated by other cytokines such as IL-18, IL-2 and  GM-CSF.

The awareness of the high porosity, nanostructure and interconnected pores in biomaterials was applied to the new FGM biomaterial. Nanosynt has micro- and nano-structured pores aligned with HA and β-TCP crystals on nanometric scale. Images obtained of the Nanosynt surface show that the HA and β-TCP nanocrystals have an average size of 200nm (Figures 2 and 3). The union of those nanocrystals form an intricate network of connected Nano and micro pores, which elevates even more the surface area and the porosity of the FGM biomaterial. With that organization, Nanosynt presents around 80 to 90% of porosity in its surface, which guarantees excellent wettability.

Those surface characteristics grant Nanosynt a greater capacity to form bone tissue when compared to other biomaterials with micro-structured surfaces. In a study carried out at the Universidade Federal Fluminense (manuscript in press) with patients from varied age groups, Nanosynt showed to be more efficient than a similar synthetic bone graft which is widely known on the market. Nanosynt showed up to 20% higher bone formation when compared to the other biomaterial and around 40% greater when compared to the control group (clot). The greater bone formation rate can also be noted when Nanosynt is compared to biomaterials of bovine origin. A study carried out with rabbits showed that when compared to the most traditional bone substitutes on the market (synthetic and bovine) Nanosynt has proven to be more efficient than both8. Four weeks after the application, the group of animals that used Nanosynt showed around 23% more new bone, compared to 11% of the other synthetic biomaterial and 17% of the bovine origin biomaterial. After 8 weeks, that difference was maintained, with Nanosynt showing around 30% more new bone compared to 27% with the other synthetic biomaterial and 24% with the bovine origin biomaterial.

 

Figure 2 – FEG image of a Nanosynt sample. 200x augmentation.

Figure 3 – FEG image of Nanosynt sample. 20,000x augmentation.

 

Aspects related to the easiness of use and biomaterial prices have always marked the choice of biomaterial by the professional. The introduction of more efficient products with better results brings to the professional a new horizon to be explored. The possibility of installing an implant in a safer way in less time leads dentists to search for alternatives to the options that have not improved much over the last decade. The technological advancement is achieved with the application of new technologies aggregated to the knowledge of biochemical processes of cellular signaling that regulate the formation of new tissues.

REFERENCES

1- Deligianni DD, Katsala ND, Koutsoukos PG, Missirlis YF. Effect of surface roughness of hydroxyapatite on human bone marrow cell adhesion, proliferation, differentiation and detachment strength. Biomaterials. 2001 Jan;22(1):87-
2- Kubinová, S.; Syková, E. Nanotechnologies in regenerative medicine. Minim. Invasive Ther. Allied Technol. 2010, 19, 144–156.
3- Laquerriere P, Grandjean-Laquerriere A, Jallot E, Balossier G, Frayssinet P, Guenounou M. Importance of hydroxyapatite particles characteristics on cytokines production by human monocytes in vitro. Biomaterials. 2003 Jul;24(16):2739-47.
4- Grandjean-Laquerriere A, Laquerriere P, Laurent-Maquin D, Guenounou M, Phillips TM. The effect of the physical characteristics of hydroxyapatite particles on human monocytes IL-18 production in vitro. Biomaterials. 2004 Dec; 25(28):5921-7.
5-Yamada N, Niwa S, Tsujimura T, Iwasaki T, Sugihara A, Futani H, Hayashi S, Okamura H, Akedo H, Terada N. Interleukin-18 and interleukin-12 synergistically inhibit osteoclastic bone-resorbing activity. Bone. 2002 Jun;30(6):901-8.
6-Costa-Rodrigues J, Silva A, Santos C, Almeida MM, Costa ME, Fernandes MH. Complex effect of hydroxyapatite nanoparticles on the differentiation and functional activity of human pre-osteoclastic cells. J Biomed Nanotechnol. 2014 Dec;10(12):3590-600.
7- Grandjean-Laquerriere A, Laquerriere P, Laurent-Maquin D, Guenounou M, Phillips TM. Biomaterials. The effect of the physical characteristics of hydroxyapatite particles on human monocytes IL-18 production in vitro. 2004 Dec;25(28):5921-7.

 

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