To promote healing of many orthopedic injuries, tissue engineering approaches are being developed that combine growth factors such as Bone Morphogenetic Proteins (BMP) with biomaterial carriers. Although these technologies have shown great promise, they still face limitations. We describe a generalized approach to create target-specific modular peptides that bind growth factors to implantable biomaterials. These bifunctional peptide coatings provide a novel way to modulate biology on the surface of an implant. Using phage display techniques, we have identified peptides that bind with high affinity to BMP-2. The peptides that bind to BMP-2 fall into two different sequence clusters. The first cluster of peptide sequences contains the motif W-X-X-F-X-X-L (where X can be any amino acid) and the second cluster contains the motif F-P-L-K-G. We have synthesized bifunctional peptide linkers that contain BMP-2 and collagen-binding domains. Using a rat ectopic bone formation model, we have injected rhBMP-2 into a collagen matrix with or without a bifunctional BMP-2: collagen peptide (BC-1). The presence of BC-1 significantly increased osteogenic cellular activity, the area of bone formed, and bone maturity at the site of injection. Our results suggest that bifunctional peptides that can simultaneously bind to a growth factor and an implantable biomaterial can be used to control the delivery and release of growth factors at the site of implantation.
References
[1]
(2000) Musculoskeletal injuries report: incidence, risk factors and prevention. Rosemont, IL: American Academy of Orthopaedic Surgeons.
[2]
Lissenberg-Thunnissen S, de Gorter D, Sier C, Schipper I (2011) Use and efficacy of bone morphogenetic proteins in fracture healing. International Orthopaedics 35: 1271–1280.
[3]
Bragdon B, Moseychuk O, Saldanha S, King D, Julian J, et al. (2011) Bone Morphogenetic Proteins: A critical review. Cellular Signalling 23: 609–620.
[4]
Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, et al. (2002) Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. The Journal of bone and joint surgery American volume 84-A: 2123–2134.
[5]
Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, et al. (2001) Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. The Journal of bone and joint surgery American volume 83-A Suppl 1S151–158.
[6]
Seeherman H, Wozney JM (2005) Delivery of bone morphogenetic proteins for orthopedic tissue regeneration. Cytokine Growth Factor Rev 16: 329–345.
[7]
Seeherman H, Wozney J, Li R (2002) Bone morphogenetic protein delivery systems. Spine 27: S16–23.
[8]
Epstein N (2011) Pros, cons, and costs of INFUSE in spinal surgery. Surgical Neurology International 2: 10–10.
[9]
Carragee EJ, Hurwitz EL, Weiner BK (2011) A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: emerging safety concerns and lessons learned. The spine journal: official journal of the North American Spine Society 11: 471–491.
[10]
Edwards RB 3rd, Seeherman HJ, Bogdanske JJ, Devitt J, Vanderby R Jr, et al. (2004) Percutaneous injection of recombinant human bone morphogenetic protein-2 in a calcium phosphate paste accelerates healing of a canine tibial osteotomy. J Bone Joint Surg Am 86-A: 1425–1438.
[11]
Luginbuehl V, Meinel L, Merkle HP, Gander B (2004) Localized delivery of growth factors for bone repair. Eur J Pharm Biopharm 58: 197–208.
[12]
Seeherman H, Li R, Wozney J (2003) A review of preclinical program development for evaluating injectable carriers for osteogenic factors. J Bone Joint Surg Am 85-A Suppl 396–108.
[13]
Seeherman H (2001) The influence of delivery vehicles and their properties on the repair of segmental defects and fractures with osteogenic factors. J Bone Joint Surg Am 83-A Suppl 1S79–81.
[14]
Andrade FK, Moreira SMG, Domingues L, Gama FMP (2010) Improving the affinity of fibroblasts for bacterial cellulose using carbohydrate-binding modules fused to RGD. Journal of Biomedical Materials Research Part A 92: 9–17.
[15]
Pertile R, Moreira S, Andrade F, Domingues L, Gama M (2012) Bacterial cellulose modified using recombinant proteins to improve neuronal and mesenchymal cell adhesion. Biotechnology progress 28: 526–532.
[16]
Lee JS, Lee JS, Murphy WL (2010) Modular peptides promote human mesenchymal stem cell differentiation on biomaterial surfaces. Acta biomaterialia 6: 21–28.
[17]
Lee JS, Lee JS, Wagoner-Johnson A, Murphy WL (2009) Modular Peptide Growth Factors for Substrate-Mediated Stem Cell Differentiation. Angewandte Chemie 121: 6384–6387.
[18]
Lee JS, Wagoner-Johnson AJ, Murphy WL (2010) A Modular, Hydroxyapatite-Binding Version of Vascular Endothelial Growth Factor. Advanced Materials 22: 5494–5498.
[19]
Hyde-DeRuyscher R, Paige LA, Christensen DJ, Hyde-DeRuyscher N, Lim A, et al. (2000) Detection of small-molecule enzyme inhibitors with peptides isolated from phage-displayed combinatorial peptide libraries. Chemistry & biology 7: 17–25.
[20]
Sparks AB, Adey NB, Cwirla S, Kay BK (1996) Chapter 13 – Screening Phage-Displayed Random Peptide Libraries. In: Brian KK, Jill W, John McCaffertyA2 – Brian K. Kay JW, John M, editors. Phage Display of Peptides and Proteins. Burlington: Academic Press. 227–253.
[21]
Gron H, Duffin D (2008) Methods and compositions for promoting localization of pharmaceutically active agents to bone. 20080268015.Affinergy.
[22]
Sparks AB, Adey NB, Quilliam LA, Thorn JM, Kay BK (1995) Screening phage-displayed random peptide libraries for SH3 ligands. Methods Enzymol 255: 498–509.
[23]
Geiger M, Li RH, Friess W (2003) Collagen sponges for bone regeneration with rhBMP-2. Advanced drug delivery reviews 55: 1613–1629.
[24]
Kwon B, Jenis LG (2005) Carrier materials for spinal fusion. The spine journal: official journal of the North American Spine Society 5: S224–S230.
