Roshan JAMES1,2,3, Meng DENG1,2,3, Cato T. LAURENCIN1,2,3,4, Sangamesh G. KUMBAR1,2,3,4()
1. Institute for Regenerative Engineering, University of Connecticut Health Center, Farmington, CT 06030, USA; 2. New England Musculoskeletal Institute, University of Connecticut Health Center, Farmington, CT 06030, USA; 3. Department of Orthopaedic Surgery, University of Connecticut Health Center, Farmington, CT 06030, USA; 4. Department of Chemical, Materials and Biomolecular Engineering, University of Connecticut, Storrs, CT 06269, USA
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.
. Nanocomposites and bone regeneration[J]. Frontiers of Materials Science, 0, (): 342-357.
Roshan JAMES, Meng DENG, Cato T. LAURENCIN, Sangamesh G. KUMBAR. Nanocomposites and bone regeneration. Front Mater Sci, 0, (): 342-357.
other traces: Cl-, F-, K+, Sr2+, Pb2+, Zn2+, Cu2+, Fe2+
-
other traces: polysaccharides, lipids, cytokines
-
-
-
primary bone cells: osteoblasts, osteocytes, osteoclasts.
-
Tab.2
Fig.2
Fig.3
Fig.4
Fig.5
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
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