Mechanistic insights into polyphosphate-mediated osteoinduction. - PROJECT SUMMARY
There is an urgent need for the creation of cost-effective biomaterials to promote osteogenesis in situations
where injured bone is biologically impaired (e.g. non-union or critical sized defects) or when osteogenesis is
desired in tissue normally devoid of bone (e.g. spinal fusion). Currently used biomaterials include autograft,
allografts, synthetic matrices, and osteoinductive biologics. Autograft is the gold standard; however, its quantity
is limited, causes pain during harvesting, and increases cost of care. Osteoconductive allografts and synthetic
matrices with or without the addition of osteoinductive factors (e.g. BMP2), have been employed with varying
results and questionable cost-effectiveness. Rationale: We have determined that synthetic analogs of ceramic
platelet polyphosphate nanoparticles (polyP-NP, chain length 60-120 repeat units) promote ossification in-vivo -
surprisingly through endochondral ossification as opposed to primarily intramembranous ossification, as is
observed with recombinant BMP2 (rBMP2). Aims/Approach: Here, we aim to determine the optimal properties,
mechanism of ossification, and potential toxicity of the abundantly available polyP-NP60-120 and to compare the
osteoinductive efficacy and toxicity to rBMP2. We will perform a definitive systematic investigation designed to
maximize the osteoinductive properties of ceramic polyP-NP60-120 (Aim 1), to determine if chondrogenesis is
essential for their angiogenic and osteoinductive properties (Aim 2), and assess whether toxic activation of
coagulation and inflammation occurs with their use (Aim 3). Osteoinductive and deleterious properties will be
compared to rBMP2. All experiments will be conducted in vivo employing the ‘Urist’ model of osteoinduction
where experimental materials are implanted into the murine gastrocnemius muscle. Anticipated results: We
anticipate that ceramic polyP-NP60-120 will possess at least equivalent osteoinductive potential as rBMP2, that
chondrogenesis is essential for polyP-NP60-120 -mediated osteoinductivity as opposed to being dispensable, as
is observed in rBMP2-mediated osteoinductivity, and that polyP-NP60-120 will cause local, but not systemic,
activation of coagulation and inflammation. Impact: If found true, these results would indicate that ceramic polyP-
NP60-120 may represent an excellent alternative to rBMP2. Specifically, if the osteoinductive properties of polyP-
NP60-120 are through a chondrocyte intermediate, it would be advantageous as chondrocytes are well equipped
to survive and produce osteoinductive factors, including VEGF and BMP2, in a vascularly devoid environments
such as the clinical situations requiring bone grafting. Additionally, given its relative availability through synthetic
routes, ceramic polyP-NP60-120 may also represent a more cost-effective alternative than isolated or recombinant
osteoinductive factors, such as rBMP2.
