(349a) Award Submission: Tunable Assembly of Biomaterials for Bone Tissue Engineering

Shah, N., David H. Koch Institute for Integrative Cancer Research at MIT
Hyder, M. N., Massachusetts Institute of Technology
Seeherman, H., Restituo LLC.
Padera, R., Brigham and Women's Hospital
Spector, M., Massachusetts Institute of Technology

Biomedical devices such as implants for total joint replacements and grafts to fill large bone defects replace native tissue, restore mobility, and alleviate morbidity. However, in some cases, these devices may fail by post-surgical loosening or stress shielding due to a modulus mismatch between the bone and implant. To attenuate these incidences, endogenous progenitor cells can be recruited to regenerate tissue to (i) promote the direct integration of the implant with the host bone tissue and (ii) repair critical size defects.  We have developed modular nanostructured coatings containing osteogenic materials, including multiple biological growth factors and inorganic bone minerals, to mimic aspects of the natural bone wound healing cascade. This enabled the formation of new, functional bone tissue which bonded a permanent prosthesis to the native tissue with superior strength and rapidly filled large defects and restored tissue strength.
     We used a layer-by-layer approach to coat implant surfaces with individual layers of materials with nanoscale control over their deposition. Angiogenic growth factor VEGF and osteoinductive growth factor BMP-2 were incorporated in gradient degradable coatings, such that VEGF released rapidly during the early acute phase of wound healing, along with slower releasing BMP-2 for longer term osteogenic effects. In vivo, coated polycaprolactone/β-tricalcium phosphate scaffolds were implanted in the rat quadriceps muscle pocket. Dual growth factor from the scaffolds surface resulted in superior de novo ectopic bone formation compared to single growth factor release as measured by µCT and histology. New bone formation was restricted to the scaffold. In a complementary study, surrogate orthopedic implants were biologically fixed to the bone tissue by recapitulating the bone matrix environment with films containing a combination of hydroxyapatite (HAP) and BMP-2. The films contained a permanent osteoconductive HAP base layer and a degradable BMP-2 releasing top layer. In vivo release of BMP-2 was monitored using fluorescence and ELISA of the marrow aspirates. In combination, HAP and BMP-2 accelerated the differentiation of human mesenchymal stem cells in vitro with concurrent upregulation of osteogenic markers. We observed that the mode and rate of growth factor release significantly influenced bone regeneration. When implanted in the rat tibia, implants bonded to the parent bone via maturing trabecular bone, with a temporal increase in the pull-out force when coated with a combination of these bone matrix materials. Long term studies indicated that the implant was stable over at least 18 months with minimal foreign body response. The interfacial tesile strength was 2-3 higher than clinically used bioactive bone cements.
     These results demonstrate that surface modification alone can be used to induce tissue regeneration. The local availability of precise amounts of regulators is as a potent tool in tissue engineering and controlling the amount and duration is critical. The layer-by-layer technique is scalable, adaptable and highly tunable which makes it promising for clinical use. Precisely assembling materials using this technique in modular nanoscale assemblies can result in a synergistic response which accelerates bone regeneration and enables implants to last their natural lifetime and scaffolds to introduce rapid bone healing.

This work was funded by the NIH (R01 AG029601) and supported in part by the NCI (P30 CA014051) and the U.S. Army Research Office (under contract W911NF-07-D-0004).