CORR Insights®: Vascularized Periosteal Flaps Accelerate Osteointegration and Revascularization of Allografts in Rats

Where Are We Now?

Bernhard Heine described the periosteum’s role in bone regeneration nearly 200 years ago, yet his findings, which confirmed the osteogenic potential of well-vascularized periosteum, remain relevant today [9]. In their study, Gallardo-Calero and colleagues [8] used an animal model to determine that vascularized autogenous periosteal flaps accelerated osseointegration, bone healing, and remodelling in allografts. The authors suggest that this approach may someday be useful in allograft reconstructions using fibular or tibial periosteal flaps.

While a well-integrated allograft can serve as a high-strength biomaterial, and an autogenous vascularized flap may improve healing and osseointegration, we must remember that this kind of graft has factors in common with organ transplantation, and there are immune system implications here that we may need to consider.

The conflict between endosteal and periosteal bone formation is always present during fracture healing. For example, in a defect model of tubular bones the intramedullary part of bone formation comprises 70% to 75% and the periosteum constitutes 25% to 30% [5]. There is no question regarding the role of the periosteal flap if it is well-vascularized and if it envelops the graft.

It is reasonable to wonder whether there is an intramedullary component to the revascularization process in an allograft. Failures of osseointegration of allografts have been attributed to several factors, mainly to immunological reactions causing, beside other responses, inadequate revascularization. The latter might be influenced by biomechanical interactions like relative micro-motion, which hinders revascularization on the one side and induces the formation of fibrous tissue caused by deformation of cell bodies on the other side [12]. Inadequate new bone formation is a consequence of both cytotoxic cell-mediated immune responses causing obstruction of the end-capillaries and a biomechanical interaction, such as micro-motion hindering revascularization and inducing fibrous tissue [1, 2, 4, 6, 12]. Lipid extraction (Na2O2) and storage in extreme cold reduces the production of antibodies, but it does not directly reduce cell-mediated immune response. By contrast, freeze-drying might reduce both, the cell-mediated immune response and the production of antibodies [6]. These issues do not seem to apply to the same degree for cancellous allografts, which revascularize more easily and quickly [1]; however, they are unsuitable in situations where a structural allograft is called for.

Where Do We Need To Go?

It seems to me that to overcome the common problems we observe in terms of the osseointegration of large, structural allografts, we will need to learn more about histocompatibility matching of these tissues [1]. Since matching of tissues is expensive and laborious, many approaches have been used to regain a portion of the osteogenic potential that is lost while processing an allograft; these include synthetic or nonimmunogenic biomaterials such as calcium phosphates, collagenous scaffolds, and even bioactive glass enriched with mesenchymal stem cells and endothelial progenitor cells [7, 10, 11].

Are the immunological differences that we observe between human patients receiving allografts adequately simulated by transplanting allografts between two experimental animals of the same breed? Knowing the valuable influence of vascularized autogenous periosteal flaps, we should also determine how much of the graft must be enveloped by the periosteum, because a large allograft of tubular bone in humans cannot be completely covered. We also do not know the result of enveloped-cancellous allografts, which probably are faster to revascularize and remodel [1]. In addition, it is important to learn whether we need to cover the entire allograft with autogenous periosteum, which, again, may be impossible, or whether it is sufficient simply to cover a portion of each host-allograft junction. Finally, I think it may be reasonable to assess whether drilling or otherwise fenestrating an allograft, obviously with one eye on not excessively weakening it, can help revascularization.

How Do We Get There?

We should learn more about histocompatibility matching of massive structural allografts. A first step could be to develop a multicenter study that compares massive structural allografts of the same blood group, followed by a second cohort with defined human leukocyte antigen matching.

In animal testing studies, future researchers should consider larger grafts when working with vascularized autogenous periosteal flaps and focus on a limited enveloping of the graft around the distal interface between graft and recipient. Additionally, researchers considering future animal studies should examine both the biomechanics and the bone biology associated with drilling or fenestrating a graft, in order to determine whether any improvements in healing potential are offset by an unacceptable amount of structural weakening caused by the creation of stress risers.

Researchers interested in developing in-vitro studies should prepare massive allografts with drilling and fenestrations measuring the reduction in strength of the graft. In the in-vivo experiment, researchers should investigate osseointegration with and without microsutured vascularized periosteal flaps of prepared allografts. Since calcium-phosphate ceramics can osseointegrate quickly, the combination of vascularized autologous periosteal flaps can be combined by enveloping those ceramics [3, 10].