New perspectives

The future of bone regeneration. Understanding its biological bases

Hard and soft tissue deficiencies are a relatively common clinical problem. Decisions concerning treatment approaches should be based primarily on the type of the defect present (see for example, the classification by Benic & Hammerle, 2014). But in order to talk about the future of bone regeneration, we must first discuss with biology.

Biological bases of bone regeneration

Due to the intramembranous ossification of the jaws, bone regeneration relies on a well-orchestrated interplay between connective and osseous tissues. Blood clots (as primary matrices), growth factors and stem cells are the three interacting players. On day seven of the regeneration process, angiogenesis is the key event indicating the start of bone formation. Direct ossification is then promoted by signalling proteins like bone morphogenetic proteins (BMPs), permitting mineralisation and, later, mature bone remodelling processes to take place. This takes time and passes through phases of proliferation, matrix maturation and mineralisation (fig 5).

The balanced mechanisms of bone signalling pathways should also be taken into account. These pathways form the well-established feedback processes of bone formation/resorption and resting/reversal of mineralisation. Furthermore, the recent discovery of the communication between osseous tissues and the immune system has been linked with the role of macrophages (fig 6). The speaker asked: would it be possible to regulate the switching between the two macrophage phenotypes?

But in an oral setting, bone defects are surrounded by biofilm which is always present in exposed surfaces and sends pro-inflammatory signals to macrophages. For bone regeneration to occur, it is necessary to keep the inflammation under control. This control comes from blood clot stability and protection of the wound via primary closure, both of which are closely related to surgical technique and flap handling (fig 7–8).

Based on all of this, how can we enhance bone regeneration?

Our first option may be cell therapies. In the future, these may soon be ready to implement; however, there is currently insufficient clinical evidence and there are high costs and regulations which are difficult to overcome today (fig 9).

A second option may be to improve the scaffolds and membranes which maintain the space, stabilise the blood clot and protect the wound. Jaw defects often have an unstable morphology and tend to be exposed to soft tissue pressures under oral functions. Considering this, bone regeneration cannot be achieved without proper membranes and scaffolds.

In the future, membranes will switch from passive barriers to bioactive carriers.

We currently do not know the real significance of cross-linking, neither can we be sure about the performance of collagen membranes that resorb quickly (since the duration has still not been fully determined in clinical scenarios). But future outlooks suggest that membranes will switch from passive barriers to being bioactive, and will release signal molecules activating cells to induce bone regeneration (fig 10).

Users and manufacturers probably don’t consider the diverse properties biomaterials require.

In general, the current market for scaffold biomaterials (i.e. users and manufacturers) do not take into account the mechanical, chemical and structural properties really required. Like membranes, biomaterials exhibit hybrid competencies beyond ongoing osseo-conduction. European authorities do not currently support research on biomaterials from cadaver donors or animals. Given this, it is reasonable to think that the future belongs to synthetic composites made of polymers and calcium-phosphate ceramics with optimised designs for macro-, micro- and even nano-structures, and fabricated as 3D printing constructs.

Should an appropriate scaffold be available, would a membrane be required?

In an experimental study using deproteinised bovine bone mineral (DBBM), the combination of membranes and DBBM had the best outcomes compared with membranes or xenografts alone (Sanz et al., 2017). In another histological study, the combination of a cross-linked membrane with synthetic bone substitute showed better results than controls using collagen membranes plus DBBM (Jung et al., 2017).

Experimental evidence points to membranes and scaffolds used together, and longer duration of the barrier membrane.

Regarding signalling molecules, after more than two decades of research, clinical use of BMPs is lacking. Platelet aggregates are increasingly applied in regenerative oral surgery as a source of growth factors. In an RCT split-mouth study it was concluded that leucocyte-platelet rich fibrin (L-PRF) was beneficial compared with natural healing of the socket (Temmerman et al., 2016). But a recent systematic review found no significant additional benefits in ridge preservation using PRF alone (Lin et al., 2019). Therefore, inconsistencies remain in the literature.

The future of bone regeneration will be a toolbox of various technologies in progress

In future, bone regeneration techniques will likely be viewed as a toolbox for combining diverse technologies. When these techniques are available, practitioners will able to use cells, scaffolds and signalling molecules to build customised bioactive constructs.