The BNS BioNanoScaffolds (BNS) is a new class of composite, biologically active Fracture Putty (FP) material, consisting of several fundamental building blocks that can be integrated in a matrix material made of poly(propylene fumarate) (PPF), which can be cured in vivo by exposure to light or by heating. Biodegradable nanoporous silicon enclosures (NSEs) are embedded into the PPF matrix to provide immediate mechanical reinforcement at a level comparable to undamaged bone. The biologically active composite "putty" material will be engineered to provide independent ambulation as early as one week after traumatic non-union fracture. The degradation of the PPF and its strengthening inclusions gradually transfer the mechanical load to the regenerating bone, aiding in its functional recovery. Our BNS is designed to actively promote and enable the self-healing of the bone and surrounding soft tissue, so that 6 months post injury, their architecture and function are fundamentally restored. To this end, to classes of molecules, which stimulate the natural regeneration of hard and soft tissue, are also incorporated within the BNS composites: 1. The self-assembling peptide amphiphiles (PA) developed by our team, and 2. A cadre of molecules that attract mesenchymal stem cells to the site of the fracture and stimulate their differentiation at the injury site. Adhesion of the fracture putty components and of the BNS to the recipient biology at application will be developed consistently with the wet conditions of traumatic injury. The release of multiple agents from the BNS is envisioned to fight infection and biofilm formation, to control pain and to promote angiogenesis and lymphatic reconstruction. Mathematical models will be used to guide in the selection of the candidate BNS from the extraordinarily vast design space available to our team. The mathematical methods to be employed include homogenization theories of our derivation, doublet mechanics, our methods for the rational design of nanomedical devices, and innovative computational approaches. The mathematically selected BNS candidates will be tested in vitro for their mechanical and biological properties. The most successful candidates will be applied to rat and rabbit models of non-union fracture in load-bearing long bone. With the experience gained in silico, in vitro, and in vivo on these models we will graduate to the sheep model, with the 18-month objective of restoring ambulation per the stipulated Phase 1 Metric one week post trauma and BNS application. Months 18-24 are dedicated to the monitoring of healthy tissue regeneration, BNS biodegradation and resorption, and gradual transfer of the load to the renewed bone.
A tightly integrated team of investigators from 7 institutions, with expertise in all of the required areas is currently involved in this research. The PI is Prof. Mauro Ferrari of the University of Texas Health Science Center in Houston (UTHSC-H), M.D. Anderson, and Rice University (silicon nanotechnology, mathematics) and the research is coordinated by Asst. Prof. Ennio Tasciotti (molecular biology, silicon nanotechnology).They are joined in this proposal by Prof. Tony Mikos and Faculty Fellow Kurtis Kasper (orthopedic biomaterials, polymer science) of Rice University, Prof. Paul Simmons of UTHSC-H (stem cells, bone biology), Prof. Samuel Stupp of Northwestern (peptide amphiphiles, tissue engineering), Prof. George Whitesides of Harvard (multi-scale chemistry, adhesion, biofilms), Prof. Theresa Fossum of TAMU (veterinary sciences), veterinary bone pathologist Prof. Roy Pool at TAMU, orthopedic surgeon Dr. Bradley Weiner of Methodist (in collaboration with Dr. Philip Noble at the Institute of Orthopedic Research and Education for clinical guidance and spinal surgery), and Dr. Mark Wong of UTHSC-H (in collaboration with Asst. Prof. Nagi Demian for clinical guidance and craniofacial surgery), Assc. Prof. Paolo Decuzzi of UTHSC-H (rational design, mechanics), Asst. Prof. Ramille Capito of Northwestern (biomaterials, peptide self assembly), Asst. Prof. Raffaella Righetti of TAMU (imaging).