InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Chemistry » "Hydroxyapatite - Advances in Composite Nanomaterials, Biomedical Applications and Its Technological Facets", book edited by Jagannathan Thirumalai, ISBN 978-953-51-3805-1, Print ISBN 978-953-51-3804-4, Published: February 14, 2018 under CC BY 3.0 license. © The Author(s).

Chapter 1

Introductory Chapter: The Testament of Hydroxyapatite: New Prospects in Regenerative Medicinal Treatments

By Jagannathan Thirumalai
DOI: 10.5772/intechopen.72767

Article top

Introductory Chapter: The Testament of Hydroxyapatite: New Prospects in Regenerative Medicinal Treatments

Jagannathan Thirumalai
Show details

1. A terse testament of hydroxyapatite

The term ‘Hydroxyapatite (HAp)’ is a naturally occurring mineral and chemically identical to the mineral constituent of bones and solid tissues of mankind and mammals. As a mineral species, apatite was first known in 1786 by “the father of German geology” Abraham Gottlob Werner (1750–1817) and entitled by him on or after the antediluvian Greek απατάω (apatao)—“to mislead” or “to deceive” since it had earlier been does not specify one chemical opus. Though, the word “apatite” was revealed in the 1990s and is denoted as calcium orthophosphate, which would be a very infrequent heterogeneity of tourmaline, beryl and other stones [1]. The period of HAp in reformative science backdate to 1950s [2] furthermore for the filling of the bone defects, the bioceramics might be used as an inert scaffold. The history related to calcium orthophosphates dates back to 1770 [3] the mistaken for other minerals, such as beryl, tourmaline, chrysolite, amethyst, fluorite, etc., [1, 4, 5]. Currently, apatite is the term for a group of minerals with the same crystallographic structure and older history till 1950 could be delivered somewhere else in the published literature [6, 7]. On the basis of thorough literature survey of HAp, since 1950 in connection to its properties, production, composition and its applications were extensively studied and its usage in medicinal disciplines contributes many breakthroughs in contemporary technological developments in consideration with the interaction of materials on active species [8]. In the origin, HAp was used for grafting, which might not have reaction with neighbouring living cells. Far ahead, the development would change to the responsive nature of the material, also for the growth of bone the reactive material pretends as a conductive scaffold [7]. In recent trend, developing fabrication technology with the dawn of recognizing of regenerative medicinal growth in the field of nanotechnology and have transformed the appearance of bioceramics to a dissimilar facet [9, 10, 11, 12, 13, 14].

Hydroxyapatite, HAp is an elementary calcium phosphate, and its chemical formula is Ca10(PO4)6(OH)2 present as main material of teeth, bones and mineral certainly with high bi-affinity. It is composited by below methods, and it is also applicable in various fields including biomaterials. In the meantime, amorphous HAp is no longer stable and could dissolve reliant on usage environment; a sintered body has been effectively used as a material in general. And, the sintered body could not dissolve so much owing to its high crystallinity. Because fusion and grain growth of each particle arose on its process stage are foreseeable, it has been hard to control configuration and grain diameter on a nanoscale impartial like initial particles of amorphous HAp. The synthesis of HAp, with its numerous morphologies, structures, and textures, has enthusing a prodigious deal of interest in academic and industrial research for numerous heterogeneous catalysis applications. In the past three decades, a numerous synthetic routes for producing HAp powders have been developed. Productions of HAp powders are classified under four different methods are enumerated in Table 1 [34].

S. No.Methods/techniquesOutcomeDrawbackRefs.
1.DryWell-crystallizedHigh temperature (1050°C in air)[15, 16]
2.WetHigh-yield, cost-effective, simple technique, and suitable for various pressure conditionsNon-crystalline and impure phase[17]
3.Co-precipitationCrystalline, high-yield, cost-effective, template-assisted & various temperatures conditionsRequires high temperature annealing to yield product[18, 19, 20]
4.Sol–gelSimple technique, low cost, crystalline natureDependent on solvent, the temperature and pH[21, 22]
5.EmulsionMore efficient, simple and particle agglomeration is less, Suitable for various surfactants, temperature conditions.Dependent on ratio of aqueous and organic phases, pH and temperature[23, 24]
6.HydrolysisSimple technique, particle agglomeration is little high, sources are texture dependentPrecursors depend strongly on pH and temperature[25]
7.HydrothermalHighly crystalline micro or nano-sized structures, well-controlled morphology and porosityRequires constant and uninterrupted temperature and pressure conditions[26, 27]
8.Alternate energy input (low-energy plasma spray)Uniform thickness, good crystallinity, well-controlled morphology, porosity, micro hardness, and fracture toughnessRequires constant, uninterrupted temperature and pressure conditions. High temp. withstanding substrates and good cleaning process[28]
9.Microwave (MW)-assistedYield of perfectly, highly crystalline, homogeneous size, porosity and morphologyRequires constant, uninterrupted temperature conditions to yield product[29]
10.Ball-millingSimplicity, reproducibility, and large-scale productionRequires high temperature annealing to yield product and little agglomeration[30]
11.SonochemicalNanosized products, elicits perfect control of morphology, porosity and sizeRequires constant, uninterrupted temperature and pressure conditions.[31]
12.Others:Yield of perfectly homogeneous size crystalline morphologyRequires organic solvents and hot zone of an electric furnace[32, 33]
a. Solvothermal process
b. Spray pyrolysis

Table 1.

Shows the key methods for the synthesis of hydroxyapatite (HAp).

2. Topical advancements in reformative medicinal treatments in the new prospects of application of nanotechnology

HAp is considered as bioceramics that signifies the enormous amount of regenerative scion material persisting in the flea market. HAp is analogous to the bony-like apatite structure and is considered to be an important inorganic constituent for bone. However, in the organic matrix HAp is circumscribed, so that the existences of HAp in the normal bone in the form of extra inorganic trace elements [3]. Ailments related to the ablative and bone surgical treatment known as the abscission or removing a part of the bone, which ultimately needs renovation through various available measures. Since, the HAp has found increasing demand in regenerative medicine as a possible auxiliary material second to auto graft. HAp could also be used in occurrences, wherever the defects or voids present in bone. This process leads to curing of blocks, or beads by employing powders of the mineral being positioned into or on the defected parts of bone. From the time when it is bioactive, it reassures the bone to spot on the problem for further orientation of growth and this procedure may perhaps be an alternate to bone or dental implants, means that it can integrate into bone or dental structures and support growth with the no breaking down or dissolving in the human body. Though, HAp is still used for this purpose today and it is also applicable for other purposes too. Numerous advancements in nanotechnology oriented reformative medicine for the overhaul or improvement of dented tissues function in several organ systems. However, most studies concern the goings-on of topical advancements in nanomaterials used in regenerative medicinal treatments [35], as summarized in Table 2 , with some more literatures in HAp, on the basis of regenerative medicine in various organ systems.

S. No.Body partNanomaterialsOutcome (type of study)Refs.
1.BonePoly(epsilon caprolactone)Improved cell attachment, proliferation, differentiation, and mineralization of osteoblasts (in vitro)[36]
Lineage restriction of progenitor cells by topographical cues (in vitro)[37]
Nanoscaled calcium phosphateLarge-sized blood vessel infiltration leads to bone formation (in vivo; canines)[38]
HAp-coated titaniumEnhanced and accelerated osseoimplant integration (in vivo; rats)[39]
Hybrid biomimetic collagen-hydroxyapatite compositesCrosslinking reactions for hard tissue engineering application with designed bioactive properties[40]
Nanostructured beta tri-calcium phosphate-coated over poly (lactic acid)Enhanced osteoconductivity of scaffold (in vitro) and heterotrophic bone formation (in vivo; rabbits)[41]
Carbon nanotubesExtracellular matrix calcification (in vitro); lamellar bone regeneration (in vivo; mice)[42]
Porous bone formation in bone defect (in vivo; rats)[43]
Silica nanofibersProliferation and maturation of MG63 cells (in vitro)[44]
2.CartilagePentosan poly sulfate in poly (ethylene glycol) HAFormation of cartilage like tissues by mesenchymal progenitor cells (in vitro)[45]
PVA/PCL [poly(vinyl alcohol) poly(caprolactone)]Proliferation and chondrogenic differentiation of MSCs (in vitro); improved healing of cartilage defects (in vivo; rabbits)[46]
3D porous polycaprolactone (PCL)-hydroxyapatite (HAp) scaffold combined with MCImproves the biological performance of 3D PCL-HAp scaffold[47]
POSS–PCU [polyhedral oligomeric silsesquioxane with polycarbonate polyurethane]Enhanced survival, proliferation, and chondrogenic differentiation of adipose tissue derived stem cells (in vitro)[48]
Enhanced growth and proliferation of nasoseptal chondrocytes (in vitro)[49]
3.Peripheral nervous systemElectrospun collagen/poly (lactic-co-glycolic acid)Axon regeneration, myelination, and action potential propagation (in vivo; rats)[50]
Poly(L-lactide-co-glycolide)/chitosan/hydroxyapatite(PLGA/chitosan/HAp)In vivo application of PLGA/chitosan/HAp conduits for nerve regeneration[51]
POSS–PCU–MWCNTNovel biomaterial capable of electronic interfacing with tissue holds potential to promote nerve regeneration[52]
4.Central nervous systemSmall interfering ribonucleic acid (Si-RNA) chitosan nanoparticlesIncreased delivery of drugs by crossing BBB (blood–brain barrier) (in vivo; rats)[53]
Nano-HAPs on the growth of human glioma U251 and SHG44 cells in vitro and in vivoNano-HAPs have an obvious antineoplastic function in vitro and in vivo. It reduces the poisonous, adverse reactions to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), strongly cooperate with certain other chemotherapy drugs, decrease the toxicity, and might become a new clinical antineoplastic drug.[54]
5.Myocardial tissue/myocardial infarction (MI)Insulin-like growth factor-1 (IGF-1) with poly(lactic-co-glycolic acid)Increased protein kinase B phosphorylation and reduced infarct size (in vivo; mice)[55]
Electrospun (hb/gel/fb) [poly(hemoglobin/gelatin/fibrinogen)]Cardiomyogenic differentiation of mesenchymal stem cells (MSCs) (in vitro)[56]
PGS [poly(glycerol sebacate)]Increased transplant cell retention and survival (in vitro)[57]
Gold nanoparticles-loaded hybrid nanofibersCardiomyogenic differentiation of MSCs; superior biological and functional properties (in vitro)[58]
Calcium hydroxyapatite–based dermal filler into the infarctInjection of an acellular dermal filler into an MI immediately after coronary occlusion reduces early infarct expansion and limits chronic LV remodeling.[59]
6.SkinSilver nanoparticlesReduced inflammation and promotion of wound healing (in vitro)[60]
Plasma-treated electrospun poly(lactic-acid) co-poly(epsilon caprolactone), and gelatinIncreased fibroblast proliferation and collagen secretion (in vitro)[61]
Titanium abutment (control) and one HA-coated abutment (case) interfaceThe HAp-coated abutment can achieve integration with the surrounding skin.[62]
Rosette nanotubes with PHeMA [poly(2-hydroxyethyl methacrylate]Increased keratinocyte and fibroblast proliferation (in vitro)[63]
7.EyePolydimethylsiloxaneTopographical cue for formation of functioning corneal endothelium (in vitro)[64]
HAp, polytetrafluoroethylene (PTFE), polyhydroxyethyl methacrylate (HEMA), and glass (control)Improving the initial cell adhesion environment in the skirt element of keratoprostheses may enhance tissue integration and reduce device failure rates.[65]
Super paramagnetic nanoparticlesIncreased gene expression and neurite growth, subcellular organelle localization, and nano therapeutics delivery (in vitro)[66]
8.LungDeferoxamineRegeneration of microvascular anastomosis in airways (in vivo; mice)[67]
HAPNs in both A549 and 16HBE cellsHAPNs might be a promising agent or mitochondria-targeted delivery system for effective lung cancer therapy.[68]
101F6 (tumor suppressor gene) nanoparticlesIncreased tumor cell lysis (in vitro and in vivo; mice)[69]

Table 2.

Topical advancements in nanomaterials used in regenerative medicinal treatments [35].

Courtesy: Reproduced from Ref. [35] with permission from Dove Medical Press, copyright 2014.

Applications of nanotechnology in regenerative medicine would require the entire prospective to reform tissue repair and regeneration [35]. Till now, to trigger the regeneration process the growth of impeccable nanomaterials accomplished of transfer signals to the diseased or damaged cells and tissues it remnants a dare. By employing nano-HAp based materials in regenerative medicine is a material of significant relate to the safety in relations to human health aspects, for the reason that this area is still in its developing platform. Erstwhile to human health based applications, a systematic research work in relevance to the noxious effect of these nanomaterials would be carrying through in excessive manner. In conclusion, at the nanoscale level to make acquainted about the original mechanisms of cell-biomaterial surface interfaces, and further implement the findings from bench to bedside, a manageable teamwork flanked by the scientists and clinicians is of highly necessary for the societal benign.

3. Conclusion

In summary, hydroxyapatite is one of the well-studied biomaterials in the medical field for its established biocompatibility and for being the main content of the mineral part of bone, teeth and various organ systems. However the fact demonstrates that it has been more imperious towards ground-breaking research against novel medical applications for the cause of the society. It has all the typical topographies of biomaterials, such as, bioactive, biocompatible, non-toxic, osteoconductive, non-immunogenic, non-inflammatory, bioceramic coatings, bone void fillers for orthopedics, dental implant coating, HAp thin films, and resemblance to the inorganic component of human beings. In the midst of the major remarkable progress are in various fields of molecular biology, biochemistry, bioinformatics, microbiology, genetics, cytometry, medical diagnostics, drug & gene delivery, and the addition of nanotechnology are the most important worldwide challenges so far. The dispute of novel spectroscopic/microscopical innovation contains interdisciplinary areas that might endure to be enhanced for these innovative global developments in x-ray imaging, spectral imaging, time-correlated single-photon counting, fluorescence quenching, endo- and exo-thermic reaction rates, kinetic chemical reaction rates, In vitro and In vivo studies, visual implants, neurology and non-invasive optical biopsy. Thus, studies towards unique nano-hydroxyapatite used in regenerative medicinal treatments might give way to mechanisms of cell-biomaterial relations at the nanoscale level that may feasibly turn out to be the upcoming forerunners to human applications in the embryonic stage.


All authors contributed towards data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work. The authors apologize for inadvertent omission of any pertinent references.

Conflict of interest

The authors declare that there is no conflict of interests regarding the publication of this paper.


1 - Dorozhkin SV. A detailed history of calcium orthophosphates from 1770s till 1950. Materials Science and Engineering: C. 2013;33(1):3085-3110. DOI: 10.1016/j.msec.2013.04.002
2 - Dubok VA. Bioceramics – Yesterday, today, tomorrow. Powder Metallurgy and Metal Ceramics. 2000;39(7-8):381-394. DOI: 10.1023/A:1026617607548
3 - Hench LL, Tompson I. Twenty-first century challenges for biomaterials. Journal of Royal Society Interface. 2010;7(Suppl 4):S379-S391. DOI: 10.1098/rsif.2010.0151.focus
4 - Dorozhkin SV. Calcium orthophosphates in nature, Biology and Medicine. Materials. 2009;2(2):399-498. DOI: 10.3390/ma2020399
5 - Dorozhkin SV. Calcium orthophosphates: Occurrence, properties, biomineralization, pathological calcification and biomimetic applications. Biomatter. 2011;1(2):121-164. DOI: 10.4161/biom.18790
6 - Weiner S, Wagner HD. The Material Bone: Structure-mechanical function relations. Annual Review of Materials Science. 1998;28(1):271-298. DOI: 10.1146/annurev.matsci.28.1.271
7 - Dorozhkin SV. Calcium Orthophosphates Applications in Nature, Biology and Medicine. 1st ed. Boca Raton: Pan Stanford Publishing; 2012. p. 870. DOI: 10.4032/9789814364171
8 - LeGeros RZ. Calcium phosphate-based osteoinductive materials. Chemical Reviews. 2008;108(11):4742-4753. DOI: 10.1021/cr800427g
9 - Ohgushi H, Dohi Y, Tamai S, Tabata S. Osteogenic differentiation of marrowstromal stem cells in porous hydroxyapatite ceramics. Journal of Biomedical Materials Research. 1993;27(11):1401-1407. DOI: 10.1002/jbm.820271107
10 - Ripamonti U, Crooks J, Khoali L, Roden L. Te induction of bone formation by coral-derived calcium carbonate/hydroxyapatite constructs. Biomaterials. 2009;30(7):1428-1439. DOI: 10.1016/j.biomaterials.2008.10.065
11 - Ripamonti U, Richter PW, Nilen RWN, Renton L. Te induction of bone formation by smart biphasic hydroxyapatite tricalcium phosphate biomimetic matrices in the non-human primate Papio ursinus. Journal of Cellular and Molecular Medicine. 2008;12(6b):1-15. DOI: 10.1111/j.1582-4934.2008.00312.x
12 - Yuan H, Kurashina K, de Bruijn JD, Li Y, de Groot K, Zhang X A preliminary study on osteoinduction of two kinds of calcium phosphate ceramics. Biomaterials 1999;20(19):1799-1806. DOI: 10.1016/S0142-9612(99)00075-7
13 - Habibovic P, Gbureck U, Doillon CJ, Bassett DC, van Blitterswijk CA, Barralet JE. Osteoconduction and osteoinduction of low-temperature 3D printed bioceramic implants. Biomaterials. 2008;29(7):944-953. DOI: 10.1016/j.biomaterials.2007.10.023
14 - Ripamonti U, Roden LC, Renton LF. Osteoinductive hydroxyapatite-coated titanium implants. Biomaterials. 2012;33(15):3813-3823. DOI: 10.1016/j.biomaterials.2012.01.050
15 - Korber F, Trömel GZ. The formation of HAP through a solid state reaction between tri and tetra – calcium phosphates. Journal of The Electrochemical Society. 1932;38:578-580
16 - Guo X, Yan H, Zhao S, Li Z, Li Y, Liang X. Effect of calcining temperature on particle size of hydroxyapatite synthesized by solid-state reaction at room temperature. Advanced Powder Technology. 2013;24(6):1034-1038. DOI: 10.1016/j.apt.2013.03.002
17 - Pramanik S, Agarwal AK, Rai KN, Garg A. Development of high strength hydroxyapatite by solid-state-sintering process. Ceramics International. 2007;33(3):419-426. DOI: 10.1016/j.ceramint.2005.10.025
18 - Ikoma T, Yamazaki A, Nakamura S, Akao M. Preparation and structure refinement of monoclinic hydroxyapatite. Journal of Solid State Chemistry. 1999;144(2):272-276. DOI: 10.1006/jssc.1998.8120
19 - Tao J, Jiang W, Pan H, Xu X, Tang R. Preparation of large-sized hydroxyapatite single crystals using homogeneous releasing controls. Journal of Crystal Growth. 2007;308(1):151-158. DOI: 10.1016/j.jcrysgro.2007.08.009
20 - Swain SK, Sarkar D. A comparative study: Hydroxyapatite spherical nanopowders and elongated nanorods. Ceramics International. 2011;37(2):2927-2930. DOI: 10.1016/j.ceramint.2011.03.077
21 - Chen J, Wang Y, Chen X, Ren L, Lai C, He W, Zhang Q. A simple sol-gel technique for synthesis of nanostructured hydroxyapatite, tricalcium phosphate and biphasic powders. Materials Letters. 2011;65(12):1923-1926. DOI: 10.1016/j.matlet.2011.03.076
22 - Rajabi-Zamani AH, Behnamghader A, Kazemzadeh A. Synthesis of nanocrystalline carbonated hydroxyapatite powder via nonalkoxide sol–gel method. Materials Science and Engineering: C. 2008;28(8):1326-1329. DOI: 10.1016/j.msec.2008.02.001
23 - Shum HC, Bandyopadhyay A, Bose S, Weitz DA. Double emulsion droplets as microreactors for synthesis of mesoporous hydroxyapatite. Chemistry of Materials. 2009;21(22):5548-5555. DOI: 10.1021/cm9028935
24 - Zhou W, Wang M, Cheung W, Guo B, Jia D. Synthesis of carbonated hydroxyapatite nanospheres through nanoemulsion. Journal of Materials Science. Materials in Medicine. 2008;19(1):103-110. DOI: 10.1007/s10856-007-3156-9
25 - Sturgeon JL, Brown PW. Effects of carbonate on hydroxyapatite formed from CaHPO4 and Ca4(PO4)2O. Journal of Materials Science. Materials in Medicine. 2009;20(9):1787-1794. DOI: 10.1007/s10856-009-3752-y
26 - Lin K, Liu X, Chang J, Zhu Y. Facile synthesis of hydroxyapatite nanoparticles, nanowires and hollow nano-structured microspheres using similar structured hard-precursors. Nanoscale. 2011;3(8):3052-3055. DOI: 10.1039/c1nr10334b
27 - Thirumalai J, Chandramohan R, Vijayan TA. Synthesis, characterization and growth mechanism of dumbbell-shaped Fluoroapatite (FHAp) superstructures. Advanced Science Letters. 2012;5(1):118-123. DOI: 10.1166/asl.2012.1925
28 - Garcia-Alonso D, Parco M, Stokes J, Looney L. Low-Energy Plasma Spray (LEPS) deposition of hydroxyapatite/poly-e-Caprolactone biocomposite coatings. Journal of Thermal Spray Technology. 2012;21(1):132-143. DOI: 10.1007/s11666-011-9695-0
29 - Farzadi A, Solati-Hashjin M, Bakhshi F, Aminian A. Synthesis and characterization of hydroxyapatite/β-tricalcium phosphate nanocomposites using microwave irradiation. Ceramics International. 2011;37(1):65-71. DOI:
30 - El Briak-Benabdeslam H, Ginebra MP, Vert M, Boudeville P. Wet or dry mechanochemical synthesis of calcium phosphates? Influence of the water content on DCPD–CaO reaction kinetics. Acta Biomaterialia. 2008;4(2):378-386. DOI: 10.1016/j.actbio.2007.07.003
31 - Giardina MA, Fanovich MA. Synthesis of nanocrystalline hydroxyapatite from Ca(OH)2 and H3PO4 assisted by ultrasonic irradiation. Ceramics International. 2010;36(6):1961-1969. DOI: 10.1016/j.ceramint.2010.05.008
32 - Smolen D, Chudoba T, Malka I, Kedzierska A, Lojkowski W, Swieszkowski W, Kurzydlowski KJ, Kolodziejczyk-Mierzynska M, Lewandowska-Szumie M. Highly biocompatible, nanocrystalline hydroxyapatite synthesized in a solvothermal process driven by high energy density microwave radiation. International Journal of Nanomedicine. 2013;8(1):653-668. DOI: 10.2147/IJN.S39299
33 - Cho JS, Lee JC, Rhee SH. Effect of precursor concentration and spray pyrolysis temperature upon hydroxyapatite particle size and density. Journal of Biomedical Materials Research. Part B, Applied Biomaterials. 2016;104(2):422-430. DOI: 10.1002/jbm.b.33406
34 - Fihri A, Len C, Varma RS, Solhy A. Hydroxyapatite: A review of syntheses, structure and applications in heterogeneous catalysis. Coordination Chemistry Reviews. 2017;347(9):48-76. DOI: 10.1016/j.ccr.2017.06.009
35 - Chaudhury K, Kumar V, Kandasamy J, RoyChoudhury S. Regenerative nanomedicine: Current perspectives and future directions. International Journal of Nanomedicine. 2014;9(1):4153-4167. DOI: 10.2147/IJN.S45332
36 - Wang J, Valmikinathan CM, Liu W, Laurencin CT, Yu X. Spiral structured, nanofibrous, 3D scaffolds for bone tissue engineering. Journal of Biomedical Materials Research. Part A. 2010;93(2):753-762. DOI: 10.1002/jbm.a.32591
37 - Cassidy JW, Roberts JN, Smith CA, Robertson M, White K, Biggs MJ, Oreffo RO, Dalby MJ. Osteogenic lineage restriction by osteoprogenitors cultured on nanometric grooved surfaces: The role of focal adhesion maturation. Acta Biomaterialia. 2014;10(2):651-660. DOI: 10.1016/j.actbio.2013.11.008
38 - Appleford MR, Oh S, Oh N, Ong JL. In vivo study on hydroxyapatite scaffolds with trabecular architecture for bone repair. Journal of Biomedical Materials Research. Part A. 2009;89(4):1019-1027. DOI: 10.1002/jbm.a.32049
39 - Yamada M, Ueno T, Tsukimura N, et al. Bone integration capability of nanopolymorphic crystalline hydroxyapatite coated on titanium implants. International Journal of Nanomedicine. 2012;7(1):859-873. DOI: 10.2147/IJN.S28082
40 - Krishnakumar GS, Gostynska N, Dapporto M, Campodoni E, Montesi M, Panseri S, Tampieri A, Kon E, Marcacci M, Sprio S, Sandric M. Evaluation of different crosslinking agents on hybrid biomimetic collagen-hydroxyapatite composites for regenerative medicine. International Journal of Biological Macromolecules. 2017;106:739-748. DOI: 10.1016/j.ijbiomac.2017.08.076
41 - Cao L, Duan PG, Wang HR, et al. Degradation and osteogenic potential of a novel poly(lactic acid)/nano-sized β-tricalcium phosphate scaffold. International Journal of Nanomedicine. 2012;7(1):5881-5888. DOI: 10.2147/IJN.S38127
42 - Lobo AO, Siqueira IA, Das Neves MF, Marciano FR, Corat EJ, Corat MA. In vitro and in vivo studies of a novel nanohydroxyapatite/superhydrophilic vertically aligned carbon nanotube nanocomposites. Journal of Materials Science. Materials in Medicine. 2013;24(7):1723-1732. DOI: 10.1007/s10856-013-4929-y
43 - Hirata E, Ménard-Moyon C, Venturelli E, et al. Carbon nanotubes functionalized with fibroblast growth factor accelerate proliferation of bone marrow-derived stromal cells and bone formation. Nanotechnology. 2013;24(43):435101. DOI: 10.1088/0957-4484/24/43/435101
44 - Ravichandran R, Gandhi S, Sundaramurthi D, Sethuraman S, Krishnan UM. Hierarchical mesoporous silica nanofibers as multifunctional scaffolds for bone tissue regeneration. Journal of Biomaterials Science. Polymer Edition. 2013;24(17):1988-2005. DOI: 10.1080/09205063.2013.816930
45 - Frith JE, Cameron AR, Menzies DJ, et al. An injectable hydrogel incorporating mesenchymal precursor cells and pentosan polysulphate for intervertebral disc regeneration. Biomaterials. 2013;34(37):9430-9440. DOI: 10.1016/j.biomaterials.2013.08.072
46 - Shafee A, Soleimani M, Chamheidari GA, et al. Electrospun nanofberbased regeneration of cartilage enhanced by mesenchymal stem cells. Journal of Biomedical Materials Research. Part A. 2011;99(3):467-478. DOI: 10.1002/jbm.a.33206
47 - Yao Q, Wei B, Liu N, Li C, Guo Y, Shamie AN, Chen J, Tang C, Jin C, Xu Y, Bian X, Zhang X, Wang L. Chondrogenic regeneration using bone marrow clots and a porous polycaprolactone-hydroxyapatite scaffold by three-dimensional printing. Tissue Engineering. Part A. 2015;21(7-8):1388-1397. DOI: 10.1089/ten.TEA.2014.0280
48 - Guasti L, Vagaska B, Bulstrode NW, Seifalian AM, Ferretti P. Chondrogenic differentiation of adipose tissue-derived stem cells within nanocaged POSS-PCU scaffolds: A new tool for nanomedicine. Nanomedicine. 2014;10(2):279-289. DOI: 10.1016/j.nano.2013.08.006
49 - Oseni AO, Butler PE, Seifalian AM. The application of POSS nanostructures in cartilage tissue engineering: The chondrocyte response to nanoscale geometry. Journal of Tissue Engineering and Regenerative Medicine. 2015;9(11):E27-E38. DOI: 10.1002/term.1693
50 - Ouyang Y, Huang C, Zhu Y, Fan C, Ke Q. Fabrication of seamless electrospun collagen/PLGA conduits whose walls comprise highly longitudinal aligned nanofibers for nerve regeneration. Journal of Biomedical Nanotechnology. 2013;9(6):931-943. DOI: 10.1166/jbn.2013.1605
51 - Shen X, Ruan J, Zhou Z, Zeng Z, Xie L. Evaluation of PLGA/chitosan/HA conduits for nerve tissue reconstruction. Journal of Wuhan University of Technology-Materials Science Edition. 2009;24(4):566-570. DOI: 10.1007/s11595-009-4566-y
52 - Antoniadou EV, Ahmad RK, Jackman RB, Seifalian AM. Next generation brain implant coatings and nerve regeneration via novel conductive nanocomposite development. In: Nigel Lovell, editor. Conference proceedings IEEE Engineering in Medicine and Biology Society, EMBC, 2011 annual international conference of the IEEE; 30 August 3 – September 2011; Boston, MA: IEEE; 2011. pp. 3253-3257. DOI: 10.1109/IEMBS.2011.6090884
53 - Malmo J, Sandvig A, Vårum KM, Strand SP. Nanoparticle mediated P-glycoprotein silencing for improved drug delivery across the blood–brain barrier: A siRNA-chitosan approach. PLoS One. 2013;8(1):e54182. DOI: 10.1371/journal.pone.0054182
54 - Chu SH, Feng DF, Ma YB, Li Z-Q. Hydroxyapatite nanoparticles inhibit the growth of human glioma cells in vitro and in vivo. International Journal of Nanomedicine. 2012;7(7):3659-3666. DOI: 10.2147/IJN.S33584
55 - Chang MY, Yang YJ, Chang CH, et al. Functionalized nanoparticles provide early cardioprotection after acute myocardial infarction. Journal of Controlled Release. 2013;170(2):287-294. DOI: 10.1016/j.jconrel.2013.04.022
56 - Ravichandran R, Seitz V, Reddy Venugopal J, et al. Mimicking native extracellular matrix with phytic acid-crosslinked protein nanofibers for cardiac tissue engineering. Macromolecular Bioscience. 2013;13(3):366-375. DOI: 10.1002/mabi.201200391
57 - Ravichandran R, Venugopal JR, Sundarrajan S, Mukherjee S, Sridhar R, Ramakrishna S. Minimally invasive injectable short nanofibers of poly(glycerol sebacate) for cardiac tissue engineering. Nanotechnology. 2012;23(38):385102. DOI: 10.1088/0957-4484/23/38/385102
58 - Ravichandran R, Sridhar R, Venugopal JR, Sundarrajan S, Mukherjee S, Ramakrishna S. Gold nanoparticle loaded hybrid nanofibers for cardiogenic differentiation of stem cells for infarcted myocardium regeneration. Macromolecular Bioscience. 2014;14(4):515-525. DOI: 10.1002/mabi.201300407
59 - Ryan LP, Matsuzaki K, Noma M, Jackson BM, Eperjesi TJ, Plappert TJ, St. John-Sutton MG, Gorman JH, Gorman RC. Dermal filler injection: A novel approach for limiting infarct expansion. The Annals of Thoracic Surgery. 2009;87(1):148-155. DOI: 10.1016/j.athoracsur.2008.09.028
60 - Wu J, Zheng Y, Song W, et al. Situ synthesis of silver-nanoparticles/bacterial cellulose composites for slow-released antimicrobial wound dressing. Carbohydrate Polymers. 2014;102(2):762-771. DOI: 10.1016/j.carbpol.2013.10.093
61 - Chandrasekaran AR, Venugopal J, Sundarrajan S, Ramakrishna S. Fabrication of a nanofibrous scaffold with improved bioactivity for culture of human dermal fibroblasts for skin regeneration. Biomedical Materials. 2011;6(1):015001
62 - Hoof MV, Wigren S, Duimel H, Savelkoul PHM, Flynn M, Stokroos RJ. Can the hydroxyapatite-coated skin-penetrating abutment for bone conduction hearing implants integrate with the surrounding skin? Frontiers in Surgery. 2015;2(1):1-8. DOI: 10.3389/fsurg.2015.00045
63 - Sun L, Li D, Hemraz UD, Fenniri H, Webster TJ. Self-assembled rosette nanotubes and poly (2-hydroxyethyl methacrylate) hydrogels promote skin cell functions. Journal of Biomedical Materials Research. Part A. 2014;102(10):3446-3451. DOI: 10.1002/jbm.a.35008
64 - Teo BK, Goh KJ, Ng ZJ, Koo S, Yim EK. Functional reconstruction of corneal endothelium using nanotopography for tissue-engineering applications. Acta Biomaterialia. 2012;8(8):2941-2952. DOI: 10.1016/j.actbio.2012.04.020
65 - Mehta JS, Futter CE, Sandeman SR, Faragher RGAF, Hing KA, Tanner KE, Allan BDS. Hydroxyapatite promotes superior keratocyte adhesion and proliferation in comparison with current keratoprosthesis skirt materials. Journal of Ophthalmology. 2005;89(10):1356-1362. DOI: 10.1136/bjo.2004.064147
66 - Steketee MB, Moysidis SN, Jin XL, Weinstein JE, Pita-Thomas W, Hemalatha BR, Siraj I, Jeffrey LG. Nanoparticle-mediated signalling endosome localization regulates growth cone motility and neurite growth. Proceedings of the National Academy of Sciences of the United States of America. 2011;108(47):19042-19047. DOI: 10.1073/pnas.1019624108
67 - Jiang X, Malkovskiy AV, Tian W, Sung YK, Sun W, Hsu JL, Manickam S, Wagh D, Joubert LM, Semenza GL, Rajadas J, Nicolls MR. Promotion of airway anastomotic microvascular regeneration and alleviation of airway ischemia by deferoxamine nanoparticles. Biomaterials. 2014;35(2):803-813. DOI: 10.1016/j.biomaterials.2013.09.092
68 - Sun Y, Chen Y, Ma X, Yuan Y, Liu CS, Kohn J, Qian JC. Mitochondria-targeted hydroxyapatite nanoparticles for selective growth inhibition of lung cancer in vitro and in vivo. ACS Applied Materials & Interfaces. 2016;8(39):25680-25690. DOI: 10.1021/acsami.6b06094
69 - Ohtani S, Iwamaru A, Deng W, et al. Tumor suppressor 101F6 and ascorbate synergistically and selectively inhibit non-small cell lung cancer growth by caspase-independent apoptosis and autophagy. Cancer Research. 2007;67(13):6293-6303. DOI: 10.1158/0008-5472