Controlled drug delivery for vascularization during craniofacial bone regeneration

Craniomaxillofacial (CMF) injuries have serious physical and functional consequences diminishing quality of life for ones who suffer them, as well as contributing to social and economic burdens. Compared to other public health problems, there is very little data and studies describing and characterizing the problem, especially in the military population. However, it is known that recent advances in body armor and cranial vault protection have led to increased surviving rates to battlefield injuries caused by explosions and gunshots. Battlefield injuries are characterized for being very complex open wounds that compromise not only bone, but also several soft tissues which are a key factor in successful regeneration.

Infuse® therapy by Medtronic has been accepted as the clinical standard for bone repair, although applications in the CMF region have raised many concerns due to the risks related to inflammation in the head and neck area. This has drawn great interest to the development of lower dose BMP-2 therapies to overcome safety and efficacy concerns. Therefore, with the motivation of evaluating safer therapies and answering questions about potential inflammation, heterotopic bone formation and high vascularization to ensure safer therapeutic windows for growth factors our goal was to: Evaluate spatio-temporal growth factor delivery effects on vascularization during bone tissue regeneration.

In AIM 1 we evaluated the effect of combined early and extended delivery of rhBMP-2 on the angiogenic response in a segmental mandibular bone defect model in the mini-pig. Findings suggest that early and extended delivery of rhBMP-2 therapy enhances the angiogenic response at the site of injury as well as demonstrating safety. However, although previous studies in the same model achieved bone growth, regeneration was characterized by outside bridging.

We concluded that not only the outside bridging was a concern, but also the fact that in the clinical setting delayed reconstruction (especially in the case of CMF battlefield injuries) is an extremely challenging scenario. Therefore, in AIM 2 we evaluated bone regeneration using controlled spatio-temporal delivery of rhBMP-2 in a delayed restoration in a critical sized rat calvarial defect. By increasing the local residence time of BMP-2 at the site of the injury we hope to reduce the therapeutic dose that is required currently suggested, bringing down not just the cost of the therapy but also potentially increasing its therapeutic efficacy.

Lastly, through our results and very extensive literature review of previous similar models we recognized that there are still tangible concerns about the therapeutic use of rhBMP-2. There is a very clear need to develop new therapies using well controlled synergies of multiple growth factors which may have less unwanted effects. Following this, in AIM 3 we developed a tunable, staged dual delivery system for IGF-1 and PDGF as an alternative to high dose BMP-2 delivery; proposing a new therapy for CMF and bone regeneration.