Controlled Release of Bone Morphogenetic Protein-2 Improves Motor Function After Traumatic Brain Injury in a Rat Model

Severe traumatic brain injury (TBI) is a life-threatening condition characterized by internal brain swelling and commonly treated using a two-stage surgical approach. The interval between surgeries, generally spaced weeks to months, is associated with secondary neurologic complications from leaving the brain unprotected. Hydrogels may reshape severe TBI treatment by enabling a single-stage surgical intervention, capable of being implanted at the initial surgery, remaining flexible to accommodate brain swelling, and calibrated to regenerate bone after brain swelling has subsided. The current study evaluated the use of a pentenoate-modified hyaluronic acid (PHA) polymer with thiolated devitalized tendon (TDVT) for calvarial bone regeneration in a rat TBI model. Additionally, PHA-TDVT hydrogels encapsulating microspheres containing bone morphogenetic protein-2 (BMP-2) were investigated to enhance bone regeneration. All hydrogel precursor formulations exhibited sufficient yield stress for surgical placement. The addition of TDVT to the crosslinked hydrogels increased the average compressive modulus. In vitro cell studies revealed that the PHA-TDVT hydrogel with the highest concentration of BMP-2 microspheres (i.e., PHA-TDVT+{micro}100) significantly improved calcium deposition and osteogenic gene expression. Minimal in vivo bone regeneration was observed for all hydrogel groups; however, BMP-2 microsphere addition fortuitously reduced motor skill impairment and brain atrophy. The PHA-TDVT+{micro}100 group had 2.8 times greater reach index and 2.3 times lower brain atrophy values compared to the negative control (p<0.05). Overall, hydrogels with controlled release of BMP-2 may provide neuroprotective benefits in TBI treatment. Future studies should explore BMP-2 delivery strategies to enhance both bone and brain recovery in rat TBI studies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/649206v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@136d4d4org.highwire.dtl.DTLVardef@cee564org.highwire.dtl.DTLVardef@13612e8org.highwire.dtl.DTLVardef@1134b4c_HPS_FORMAT_FIGEXP M_FIG C_FIG Statement of SignificanceSevere traumatic brain injury (TBI) is a life-threatening condition characterized by internal brain swelling and is commonly treated using a two-stage surgical approach. Complications associated with the two-stage treatment paradigm include secondary neurologic impairment, termed syndrome of the trephined (SOT). SOT is often reversible once the second surgery is performed, whereas a single-stage TBI treatment paradigm may avoid the occurrence of SOT altogether. Utilizing hydrogels comprised of pentenoate-modified hyaluronic acid and thiolated devitalized tendon encapsulating microspheres containing bone morphogenetic protein-2 (BMP-2), the current study demonstrated improvements in motor skill function and reductions in brain atrophy in a rat TBI model. The introduction of hydrogels with controlled release of BMP-2 as a neuroprotective strategy for TBI application offers a promising approach for single-stage TBI treatment.