Nanocomposites and bone regeneration

Abstract

This manuscript focuses on bone repair/regeneration using tissue engineering strategies, and highlights nanobiotechnology developments leading to novel nanocomposite systems. About 6.5 million fractures occur annually in USA, and about 550,000 of these individual cases required the application of a bone graft. Autogenous and allogenous bone have been most widely used for bone graft based therapies; however, there are significant problems such as donor shortage and risk of infection. Alternatives using synthetic and natural biomaterials have been developed, and some are commercially available for clinical applications requiring bone grafts. However, it remains a great challenge to design an ideal synthetic graft that very closely mimics the bone tissue structurally, and can modulate the desired function in osteoblast and progenitor cell populations. Nanobiomaterials, specifically nanocomposites composed of hydroxyapatite (HA) and/or collagen are extremely promising graft substitutes. The biocomposites can be fabricated to mimic the material composition of native bone tissue, and additionally, when using nano-HA (reduced grain size), one mimics the structural arrangement of native bone. A good understanding of bone biology and structure is critical to development of bone mimicking graft substitutes. HA and collagen exhibit excellent osteoconductive properties which can further modulate the regenerative/healing process following fracture injury. Combining with other polymeric biomaterials will reinforce the mechanical properties thus making the novel nano-HA based composites comparable to human bone. We report on recent studies using nanocomposites that have been fabricated as particles and nanofibers for regeneration of segmental bone defects. The research in nanocomposites, highlight a pivotal role in the future development of an ideal orthopaedic implant device, however further significant advancements are necessary to achieve clinical use.

Keywords

bone graft substitute / nanocomposite / hydroxyapatite / collagen / nanofiber / biomimetic / nanobiomaterial / osteogenic / segmental defect / tibia defect

References

[1] Braddock M, Houston P, Campbell C, . Born again bone: tissue engineering for bone repair. News in Physiological Sciences , 2001, 16(5): 208-213
[2] Shors E C. Coralline bone graft substitutes. Orthopedic Clinics of North America , 1999, 30(4): 599-613
[3] Webster T J. Nanophase ceramics as improved bone tissue engineering materials. American Ceramic Society Bulletin , 2003, 82(6): 23-28
[4] Orthopaedic Biomaterials Market Review.
[5] American Academy of Orthopaedic Surgeons. The Evolving Role of Bone-Graft Substitutes. AAOS 77th Annual Meeting, New Orleans, LA, USA , 2010. http://www.aatb.org/aatb/files/ccLibraryFiles/Filename/000000000322/BoneGraftSubstitutes2010.pdf
[6] Tomford W W. Overview. In: Laurencin C T, ed. Bone Graft Substitutes. West Conshohocken, PA , USA: ASTM International, 2003
[7] Khan Y, Laurencin C T. Fracture repair with ultrasound: clinical and cell-based evaluation. The Journal of Bone and Joint Surgery (American Volume) , 2008, 90(Suppl 1): 138-144
[8] Laurencin C, Khan Y, El-Amin S F. Bone graft substitutes. Expert Review of Medical Devices , 2006, 3(1): 49-57
[9] Ilan D I, Ladd A L. Bone graft substitutes. Operative Techniques in Plastic and Reconstructive Surgery , 2002, 9(4): 151-160
[10] Laurencin C T, Khan Y. Bone graft substitute materials. http://emedicinemedscapecom/article/1230616-overview.
[11] Goulet J A, Senunas L E, DeSilva G L, . Autogenous iliac crest bone graft. Complications and functional assessment. Clinical Orthopaedics and Related Research , 1997, 339: 76-81
[12] Berrey B H Jr, Lord C F, Gebhardt M C, . Fractures of allografts. Frequency, treatment, and end-results. The Journal of Bone and Joint Surgery (American Volume) , 1990, 72(6): 825-833
[13] Ito H, Koefoed M, Tiyapatanaputi P, . Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy. Nature Medicine , 2005, 11(3): 291-297
[14] Laurencin C T, Ambrosio A M A, Borden M D, . Tissue engineering: orthopedic applications. Annual Review of Biomedical Engineering , 1999, 1(1): 19-46
[15] Langer R, Vacanti J P. Tissue engineering. Science , 1993, 260(5110): 920-926
[16] Langer R. Tissue engineering. Molecular Therapy , 2000, 1(1): 12-15
[17] Khan Y, Yaszemski M J, Mikos A G, . Tissue engineering of bone: material and matrix considerations. The Journal of Bone and Joint Surgery (American Volume) , 2008, 90(Suppl 1): 36-42
[18] Athanasiou K A, Zhu C F, Lanctot D R, . Fundamentals of biomechanics in tissue engineering of bone. Tissue Engineering , 2000, 6(4): 361-381
[19] Einhorn T A. The cell and molecular biology of fracture healing. Clinical Orthopaedics and Related Research , 1998, 355(Supplement): S7-S21
[20] Schindeler A, McDonald M M, Bokko P, . Bone remodeling during fracture repair: The cellular picture. Seminars in Cell and Developmental Biology , 2008, 19(5): 459-466
[21] Nair L S, Laurencin C T. Biodegradable polymers as biomaterials. Progress in Polymer Science , 2007, 32(8-9): 762-798
[22] Deng M, Kumbar S G, Lo K W H, . Novel polymer-ceramics for bone repair and regeneration. Recent Patents on Biomedical Engineering , 2011, 4(3) (in press)
[23] Deng M, Kumbar S G, Wan Y, . Polyphosphazene polymers for tissue engineering: an analysis of material synthesis, characterization and applications. Soft Matter , 2010, 6(14): 3119-3132
[24] Deng M, Nair L S, Nukavarapu S P, . Dipeptide-based polyphosphazene and polyester blends for bone tissue engineering. Biomaterials , 2010, 31(18): 4898-4908
[25] Deng M, Nair L S, Nukavarapu S P, . Biomimetic, bioactive etheric polyphosphazene-poly(lactide-co-glycolide) blends for bone tissue engineering. Journal of Biomedical Materials Research Part A , 2010, 92(1): 114-125
[26] Deng M, Nair L S, Nukavarapu S P, . Miscibility and in vitro osteocompatibility of biodegradable blends of poly[(ethyl alanato) (p-phenyl phenoxy) phosphazene] and poly(lactic acid-glycolic acid). Biomaterials , 2008, 29(3): 337-349
[27] Deng M, Nair L S, Nukavarapu S P, . In situ porous structures: a unique polymer erosion mechanism in biodegradable dipeptide-based polyphosphazene and polyester blends producing matrices for regenerative engineering. Advanced Functional Materials , 2010, 20(17): 2743-2957
[28] Kierszenbaum A L. Connective tissue. In: Kierszenbaum A L, ed. Histology and Cell Biology: An Introduction to Pathology. St . Louis: Mosby Inc., 2002, 118-129
[29] Jee W S S. Integrated bone tissue physiology: anatomy and physiology. In: Cowin S C, ed. Bone Mechanics Handbook. Boca Raton, FL , USA: CRC Press LLC, 2001
[30] Rho J-Y, Kuhn-Spearing L, Zioupos P. Mechanical properties and the hierarchical structure of bone. Medical Engineering & Physics , 1998, 20(2): 92-102
[31] Murugan R, Ramakrishna S. Development of nanocomposites for bone grafting. Composites Science and Technology , 2005, 65(15-16): 2385-2406
[32] Weiner S, Wagner H D. The material bone: structure-mechanical function relations. Annual Review of Materials Science , 1998, 28(1): 271-298
[33] Marotti G. A new theory of bone lamellation. Calcified Tissue International , 1993, 53(Suppl 1): S47-S56
[34] Bilezikian J P, Raisz L G, Rodan G A. Principles of Bone Biology. San Diego, CA , USA: Academic Press, 1996
[35] Wiesmann H P, Meyer U, Plate U, . Aspects of collagen mineralization in hard tissue formation. International Review of Cytology , 2004, 242: 121-156
[36] van der Rest M, Garrone R. Collagen family of proteins. The FASEB Journal , 1991, 5(13): 2814-2823
[37] Weiner S, Traub W. Bone structure: from angstroms to microns. The FASEB Journal , 1992, 6(3): 879-885
[38] Landis W J. The strength of a calcified tissue depends in part on the molecular structure and organization of its constituent mineral crystals in their organic matrix. Bone , 1995, 16(5): 533-544
[39] Ziv V, Weiner S. Bone crystal sizes: a comparison of transmission electron microscopic and X-ray diffraction line width broadening techniques. Connective Tissue Research , 1994, 30(3): 165-175
[40] Rey C, Miquel J L, Facchini L, . Hydroxyl groups in bone mineral. Bone , 1995, 16(5): 583-586
[41] Sommerfeldt D, Rubin C. Biology of bone and how it orchestrates the form and function of the skeleton. European Spine Journal , 2001, 10(Suppl 2): S86-S95
[42] Beddington R S, Robertson E J. Axis development and early asymmetry in mammals. Cell , 1999, 96(2): 195-209
[43] Aubin J E. Bone stem cells. Journal of Cellular Biochemistry, Supplement , 1998, 72(Suppl 30-31): 73-82
[44] Ferrari S L, Traianedes K, Thorne M, . A role for N-cadherin in the development of the differentiated osteoblastic phenotype. Journal of Bone and Mineral Research , 2000, 15(2): 198-208
[45] Lecanda F, Towler D A, Ziambaras K, . Gap junctional communication modulates gene expression in osteoblastic cells. Molecular Biology of the Cell , 1998, 9(8): 2249-2258
[46] Liu X, Ma P X. Polymeric scaffolds for bone tissue engineering. Annals of Biomedical Engineering , 2004, 32(3): 477-486
[47] Li Z, Kong K, Qi W. Osteoclast and its roles in calcium metabolism and bone development and remodeling. Biochemical and Biophysical Research Communications , 2006, 343(2): 345-350
[48] Blair H C, Teitelbaum S L, Ghiselli R, . Osteoclastic bone resorption by a polarized vacuolar proton pump. Science , 1989, 245(4920): 855-857
[49] Baroli B. From natural bone grafts to tissue engineering therapeutics: Brainstorming on pharmaceutical formulative requirements and challenges. Journal of Pharmaceutical Sciences , 2009, 98(4): 1317-1375
[50] Veerman E C, Suppers R J, Klein C P, . SDS-PAGE analysis of the protein layers adsorbing in vivo and in vitro to bone substituting materials. Biomaterials , 1987, 8(6): 442-448
[51] Nojiri C, Okano T, Koyanagi H, . In vivo protein adsorption on polymers: visualization of adsorbed proteins on vascular implants in dogs. Journal of Biomaterials Science, Polymer Edition , 1993, 4(2): 75-88
[52] Davies J E. Mechanisms of endosseous integration. The International Journal of Prosthodontics , 1998, 11(5): 391-401
[53] Soultanis K, Pyrovolou N, Karamitros A, . Instrumentation loosening and material of implants as predisposal factors for late postoperative infections in operated idiopathic scoliosis. Studies in Health Technology and Informatics , 2006, 123: 559-564
[54] Kirkpatrick J S, Venugopalan R, Beck P, . Corrosion on spinal implants. Journal of Spinal Disorders & Techniques , 2005, 18(3): 247-251
[55] Laurencin C T, Khan Y, Kofron M, . The ABJS Nicolas Andry Award: Tissue engineering of bone and ligament: a 15-year perspective. Clinical Orthopaedics and Related Research , 2006, 447: 221-236
[56] Sung H J, Meredith C, Johnson C, . The effect of scaffold degradation rate on three-dimensional cell growth and angiogenesis. Biomaterials , 2004, 25(26): 5735-5742
[57] Kuboki Y, Takita H, Kobayashi D, . BMP-induced osteogenesis on the surface of hydroxyapatite with geometrically feasible and nonfeasible structures: topology of osteogenesis. Journal of Biomedical Materials Research , 1998, 39(2): 190-199
[58] D’Lima D D, Lemperle S M, Chen P C, . Bone response to implant surface morphology. The Journal of Arthroplasty , 1998, 13(8): 928-934
[59] Sul Y-T, Johansson C B, Petronis S, . Characteristics of the surface oxides on turned and electrochemically oxidized pure titanium implants up to dielectric breakdown: the oxide thickness, micropore configurations, surface roughness, crystal structure and chemical composition. Biomaterials , 2002, 23(2): 491-501
[60] Jarcho M. Calcium phosphate ceramics as hard tissue prosthetics. Clinical Orthopaedics and Related Research , 1981, 157 : 259-278
[61] Ducheyne P, de Groot K. In vivo surface activity of a hydroxyapatite alveolar bone substitute. Journal of Biomedical Materials Research , 1981, 15(3): 441-445
[62] Webster T J, Ergun C, Doremus R H, . Enhanced functions of osteoblasts on nanophase ceramics. Biomaterials , 2000, 21(17): 1803-1810
[63] Lee C H, Singla A, Lee Y. Biomedical applications of collagen. International Journal of Pharmaceutics , 2001, 221(1-2): 1-22
[64] Miyata T, Taira T, Noishiki Y. Collagen engineering for biomaterial use. Clinical Materials , 1992, 9(3-4): 139-148
[65] Rao K P. Recent developments of collagen-based materials for medical applications and drug delivery systems. Journal of Biomaterials Science, Polymer Edition , 1995, 7(7): 623-645
[66] Urist M R, Nilsson O, Rasmussen J, . Bone regeneration under the influence of a bone morphogenetic protein (BMP) beta tricalcium phosphate (TCP) composite in skull trephine defects in dogs. Clinical Orthopaedics and Related Research , 1987, 214: 295-304
[67] Urist M R, Peltier L F. Bone: formation by autoinduction. Clinical Orthopaedics and Related Research , 2002, 395: 4-10
[68] Sandhu H S, Boden S D. Biologic enhancement of spinal fusion. Orthopedic Clinics of North America , 1998, 29(4): 621-631
[69] Wang E A, Rosen V, D’Alessandro J S, . Recombinant human bone morphogenetic protein induces bone formation. Proceedings of the National Academy of Sciences of the United States of America , 1990, 87(6): 2220-2224
[70] Bianco P, Riminucci M, Gronthos S, . Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells , 2001, 19(3): 180-192
[71] Tiedeman J J, Connolly J F, Strates B S, . Treatment of nonunion by percutaneous injection of bone marrow and demineralized bone matrix. An experimental study in dogs. Clinical Orthopaedics and Related Research , 1991, 268: 294-302
[72] Grauer J N, Beiner J M, Kwon B K, . Bone graft alternatives for spinal fusion. BioDrugs , 2003, 17(6): 391-394
[73] Chan C K, Kumar T S, Liao S, . Biomimetic nanocomposites for bone graft applications. Nanomedicine , 2006, 1(2): 177-188
[74] Christenson E M, Anseth K S, van den Beucken J J J P, . Nanobiomaterial applications in orthopedics. Journal of Orthopaedic Research , 2007, 25(1): 11-22
[75] Webster T J, Ahn E S. Nanostructured biomaterials for tissue engineering bone. Advances in Biochemical Engineering/Biotechnology , 2007, 103: 275-308
[76] Webster T J, Siegel R W, Bizios R. Osteoblast adhesion on nanophase ceramics. Biomaterials , 1999, 20(13): 1221-1227
[77] Webster T J, Ergun C, Doremus R H, . Enhanced osteoclast-like cell functions on nanophase ceramics. Biomaterials , 2001, 22(11): 1327-1333
[78] Liao S S, Cui F Z. In vitro and in vivo degradation of mineralized collagen-based composite scaffold: nanohydroxyapatite/collagen/poly(L-lactide). Tissue Engineering , 2004, 10(1-2): 73-80
[79] Liao S S, Cui F Z, Zhang W, . Hierarchically biomimetic bone scaffold materials: nano-HA/collagen/PLA composite. Journal of Biomedical Materials Research Part B: Applied Biomaterials , 2004, 69(2): 158-165
[80] Laurencin C T, Attawia M A, Elgendy H E, . Tissue engineered bone-regeneration using degradable polymers: The formation of mineralized matrices. Bone , 1996, 19(1 Suppl): S93-S99
[81] Zhang P, Hong Z, Yu T, . In vivo mineralization and osteogenesis of nanocomposite scaffold of poly(lactide-co-glycolide) and hydroxyapatite surface-grafted with poly(L-lactide). Biomaterials , 2009, 30(1): 58-70
[82] Elias K L, Price R L, Webster T J. Enhanced functions of osteoblasts on nanometer diameter carbon fibers. Biomaterials , 2002, 23(15): 3279-3287
[83] Price R L, Waid M C, Haberstroh K M, . Selective bone cell adhesion on formulations containing carbon nanofibers. Biomaterials , 2003, 24(11): 1877-1887
[84] Mistry A S, Mikos A G, Jansen J A. Degradation and biocompatibility of a poly(propylene fumarate)-based/alumoxane nanocomposite for bone tissue engineering. Journal of Biomedical Materials Research Part A , 2007, 83(4): 940-953
[85] Horch R A, Shahid N, Mistry A S, . Nanoreinforcement of poly(propylene fumarate)-based networks with surface modified alumoxane nanoparticles for bone tissue engineering. Biomacromolecules , 2004, 5(5): 1990-1998
[86] Shi X, Hudson J L, Spicer P P, . Injectable nanocomposites of single-walled carbon nanotubes and biodegradable polymers for bone tissue engineering. Biomacromolecules , 2006, 7(7): 2237-2242
[87] Liu H, Slamovich E B, Webster T J. Increased osteoblast functions on nanophase titania dispersed in poly-lactic-co-glycolic acid composites. Nanotechnology , 2005, 16(7): S601-S608
[88] Webster T J, Smith T A. Increased osteoblast function on PLGA composites containing nanophase titania. Journal of Biomedical Materials Research Part A , 2005, 74(4): 677-686
[89] Li W J, Laurencin C T, Caterson E J, . Electrospun nanofibrous structure: a novel scaffold for tissue engineering. Journal of Biomedical Materials Research , 2002, 60(4): 613-621
[90] Nair L S, Laurencin C T. Nanofibers and nanoparticles for orthopaedic surgery applications. The Journal of Bone and Joint Surgery (American Volume) , 2008, 90(Suppl 1): 128-131
[91] Nair L S, Bhattacharyya S, Laurencin C T. Development of novel tissue engineering scaffolds via electrospinning. Expert Opinion on Biological Therapy , 2004, 4(5): 659-668
[92] Woo K M, Chen V J, Ma P X. Nano-fibrous scaffolding architecture selectively enhances protein adsorption contributing to cell attachment. Journal of Biomedical Materials Research Part A , 2003, 67(2): 531-537
[93] Pelled G, Tai K, Sheyn D, . Structural and nanoindentation studies of stem cell-based tissue-engineered bone. Journal of Biomechanics , 2007, 40(2): 399-411
[94] Huang Z-M, Zhang Y-Z, Kotaki M, . A review on polymer nanofibers by electrospinning and their applications in nanocomposites. Composites Science and Technology , 2003, 63(15): 2223-2253
[95] Ma P X, Zhang R. Synthetic nano-scale fibrous extracellular matrix. Journal of Biomedical Materials Research , 1999, 46(1): 60-72
[96] Whitesides G M, Grzybowski B. Self-assembly at all scales. Science , 2002, 295(5564): 2418-2421
[97] Zeleny J. The electrical discharge from liquid points, and a hydrostatic method of measuring the electric intensity at their surfaces. Physical Review , 1914, 3(2): 69-91
[98] Formhals A. Process and apparatus for preparing artificial threads. US Patent, 1975504, 1934
[99] Kumbar S G, James R, Nukavarapu S P, . Electrospun nanofiber scaffolds: engineering soft tissues. Biomedical Materials , 2008, 3(3): 034002
[100] Li D, Wang Y, Xia Y. Electrospinning of polymeric and ceramic nanofibers as uniaxially aligned arrays. Nano Letters , 2003, 3(8): 1167-1171
[101] Patel S, Kurpinski K, Quigley R, . Bioactive nanofibers: synergistic effects of nanotopography and chemical signaling on cell guidance. Nano Letters , 2007, 7(7): 2122-2128
[102] Ma Z, Kotaki M, Inai R, . Potential of nanofiber matrix as tissue-engineering scaffolds. Tissue Engineering , 2005, 11(1-2): 101-109
[103] Deng M, James R, Laurencin C T, . Nanostructured polymeric scaffolds for orthopaedic regenerative engineering. IEEE Transactions on Nanobioscience , 2011 (in press)
[104] Kumbar S G, Nukavarapu S P, James R, . Recent patents on electrospun biomedical nanostructures: an overview. Recent Patents on Biomedical Engineering , 2008, 1(1): 68-78
[105] Bhattarai N, Edmondson D, Veiseh O, . Electrospun chitosan-based nanofibers and their cellular compatibility. Biomaterials , 2005, 26(31): 6176-6184
[106] Zhang Y, Venugopal J R, El-Turki A, . Electrospun biomimetic nanocomposite nanofibers of hydroxyapatite/chitosan for bone tissue engineering. Biomaterials , 2008, 29(32): 4314-4322
[107] Yang D, Jin Y, Zhou Y, . In situ mineralization of hydroxyapatite on electrospun chitosan-based nanofibrous scaffolds. Macromolecular Bioscience , 2008, 8(3): 239-246
[108] Schneider O D, Weber F, Brunner T J, . In vivo and in vitro evaluation of flexible, cottonwool-like nanocomposites as bone substitute material for complex defects. Acta Biomaterialia , 2009, 5(5): 1775-1784
[109] Kim H-W, Kim H-E, Knowles J C. Production and potential of bioactive glass nanofibers as a next-generation biomaterial. Advanced Functional Materials , 2006, 16(12): 1529-1535
[110] Kim H-W, Song J-H, Kim H-E. Nanofiber generation of gelatin-hydroxyapatite biomimetics for guided tissue regeneration. Advanced Functional Materials , 2005, 15(12): 1988-1994
[111] Nair L S, Bhattacharyya S, Bender J D, . Fabrication and optimization of methylphenoxy substituted polyphosphazene nanofibers for biomedical applications. Biomacromolecules , 2004, 5(6): 2212-2220
[112] Bhattacharyya S, Kumbar S G, Khan Y M, . Biodegradable polyphosphazene-nanohydroxyapatite composite nanofibers: scaffolds for bone tissue engineering. Journal of Biomedical Nanotechnology , 2009, 5(1): 69-75
[113] Bhattacharyya S, Nair L S, Singh A, . Electrospinning of poly[bis(ethyl alanato) phosphazene] nanofibers. Journal of Biomedical Nanotechnology , 2006, 2(1): 36-45
[114] Conconi M T, Lora S, Menti A M, . In vitro evaluation of poly[bis(ethyl alanato)phosphazene] as a scaffold for bone tissue engineering. Tissue Engineering , 2006, 12(4): 811-819
[115] Laurencin C T, Kumbar S G, Deng M, . Nano-structured scaffolds for regenerative engineering. In: Honorary Series in Translational Research in Biomaterials, 2010 AICHE Annual Meeting, Salt Lake City, Utah, USA , 2010
[116] Deng M, Kumbar S G, Nair L S, . Biomimetic structures: biological implications of dipeptide-substituted polyphosphazene-polyester blend nanofiber matrices for load-bearing bone regeneration. Advanced Functional Materials , 2011, 21(14): 2641-2651
[117] Place E S, Evans N D, Stevens M M. Complexity in biomaterials for tissue engineering. Nature Materials , 2009, 8(6): 457-470