‘Contents lists available at ScienceDirect Advances in Colloid and Interface Science journal homepage: www.olsevier.comflocstelcis Historical perspective Synthesis of hydroxyapatite for biomedical applications ® Aleksandra Szczes*, Lucyna Holysz, Emil Chibowski epamen of hye Cary ~ fal Phenom, Fay of Chey, Mars Cae lows Une, 20.031 Lain, ean ARTICLE INFO ABSTRACT The current need for long lasting implants and bone subtites characterized by bocompatblity, bowctity ‘and mechanical properties, without the immine rejection i a great challenge for alent, These bone feito sruetrer should be prepared for individal patients wih alta eantaled on the micrometer level Similarly, nostoxi, biocompatible targeted drug delivery systems which allow controling the rate and ‘ime period ofthe rug dtivery and simultaneously eliminating tore and side eects onthe healthy tssues, are of great ites. scaffolds and implant coatings posesing the above mentioned significant biocompadblty, bioactivity and mechanical strength. Moreover, that coué als serve as dru ceivery stems. Hyéroxyapatice (HA) which sa ‘major mineral component of vertebrate bones and teeth san excellent materi for theve purposes this erature review the bolgiallyispced sales, bone substitutes, implants characterized by discucred 1. Introduction Te is knovn that during the biomineralization processes living ‘organisms are able to crystallize and deposit wide range of minerals [1.2], Among them are calcium phosphates which are produced in vertebrates not only in normal (bones, teeth) but also pathological (ental and urinary calculus and stones, stherosclerotic lesions) calei- fications of issues [34], Types af calm phosphates vary in chemical ormulae and solubility values (Table 1) Bones are complex system composed of hydroxyapatite (HA) and type I collagen fibrils, HA amounts 70% of bones, while collagen constitutes 2096 and water around 10% [3,5,5) ‘In mammals the main mineral form isso called biological apatite, ‘which isa hydroxyl-deficient and carbonatesrich apatite with the Ca/P ratio lower than 1.67 [5.7.8 very year over 2.2 mullion people worldwide require bone grafting, surgery to repair large bone defects of critical size arising from ‘accidents, trauma or diseases (like tumour resection) [9]. Healing of such defects constiutes a common and significant problem in erthope- dic surgery. Those defects are reconstructed using autologous bone afl, allografts snd biocompatible synthetic material 10). Because of| longer the life span and the fact that more implants are needed to be placed in younger patients, preparation of long lasting implants is necessary. Hence, the demand for new technologies for such implants * Coesponding autor a Uepane of Phys Chesisty, Breed eden weceepretames hing (A Sore, Avalabeomtne 20 Api 2017 00rse46/ 2017 Heer BY. Al igh rece manufacturing increases (11) Tris known that the chemical formula and properties of synthetic hydeoxyapatite are similar to those of main inorganie constituent of hones and teeth. Hence, for some time so far this mineral has been widely applied as @ biomaterial for orthopedic and dental applications for repairing or substituting hard tissues, and also as the drug delivery systems. Synthetic biomaterials composed of HA have been extensively lavestigated to construct artificial bone grafts purely made of HA or only asthe surface coating by HA. However, apart from its bioactivity and biocompatibility, ite mechanical strength and porous structure are also important when implanted into the human body (12.13). More over, there should be proper osteoconduetive, osteoinduetive and osteoincegrative properties of the material [13], Similarity of hydroxyapatite to the inorganic component of bone matrix contributes to the development of manufaeturing methods of synthetic IA preparation which can be biomedical applied applications to repair hard tissues or as drug delivery systems. The use of HA 25 2 hone substitute oF replacement includes complete or partial bone sugmentation, filling bones and teeth or coating in orthopaedics and dental implants This paper focuses on the literature recent investigations of the ‘methods of HA preparation for various biomedical applieations Le. a bone fillers and tissue engineering scaffolds, implants costing prepare Lon, and the drug delivery systems (ig, 1) (14)sable ‘Man cela porphat i 5). an Kane ‘Symtel Ferma kas ° Dem paras apie ene) bora ooo es Dance pberiate oc POaSH.O bee : ceo pharphat= omer) BS 5 Fetreaeum phoroate (sre) ms a Aamepics an papa ner PO), a140 = ff yroyapate a CntPOnctOH, hes a bone scaffold & HA bone filler, implant coating drug delivery system ig. 1. Sehemae ration of mee pple of hyconapae, 2. Bone fillers and tissue engineering scaffolds treatment of large bone defects resulting from resection of tumours, ‘trauma of infection very often requires bone grafting surgery. In the ‘ase of reconstructive procedure using autograft and allograft, the problems of donor compatibility, immune rejection and pathogen leans(er can tise. Nowadays organie/inorganie composite materials ‘ean mimic the real bones, The resultant materials of porous structare fan act aso temporary extracellular matrix, inducing the natural process of tissue regeneration and development (15-23].The improved properties of such materials result from combination of compressive strength of the inotganie ceramie phase as well as toughness and Aexibility of the polymer. Crystalline HA is known to be calcium phosphate of the slowest degradation rate if compared with the other ‘CaP phases, Purthermore, one of the mala components of bone HA is biocompatible and osteoconductve enhancing the attachment, growth, and proliferation of human osteoblast cels. Hence the incorporation of| hydroxyapatite into @ polymeric matrix is of great interest. The major factor affecting properties of such composite material i associated with the incorporation of HA into the polymer mateix, ie. nanoparticles ‘aggregation at well their adhesion to the polymer matrix. One of the methods to overcome these problems is mineral precipitation in the polymer solution Hydroxyapatite can be synthesized using different techniques such ‘as precipitation, hydrolysis, and hydrothermal synthesis (20,21,24) oF ‘extracted from natural resources, eg. fish bones [25], seashells[26] ceggshels (27,28), bovine bones {25,0 shrimp shells (29). The HA ‘content increases the compressive strength and the elastic modulus of the composite scaffolds (21|- Kim etal. (21) found that a higher content ‘of hydroxyapatite (up 0 70 wis) helped also develop more éifferentia- tion and mineralization of the MC3TS-E1 cells on the composite scaffolds. In the study of Juhasz (31) 10 wité of nano-sized needle-like HA and earbonate-substcuted hydroxyapatite (CHA) particles incorpo- rated into a poly-2-hydroxyethylmethacrylate/polycaprolactone (PIE MA/PCL) hydrogel exhibited a significantly greater eellular activity of human osteoblastlike cells on the obtained composite than the pure hydrogel and HAflle hydrogel samples ‘There ace «wo kinds of polymers used forthe scaffolds preparation natural and synthetic. Natural polymers exhibit good cellular affinicy, ‘whereas the synthetic ones contribute superior mechanical strength and aajustable degradation rate, Recently great attention has been focused on hydrogels as biopolymers due to their similarity to the extracellular fluids [32]. The most often used natuesl polymers are: ehitosan [23-85], gelatin (37-291, alginate (27,20,21,40), collagen (19,221, cellulose [39,41 and silk ibroin (42,43). Whereas asong the synthetic polymers; poly(vinyDaleohol (38,39,44,45], poly-2-hydroxyethyl- ‘methacrylate (31), polycaprolactone (31], polylacie-co-glycalie acid (IGA) [451 polylectic acid (PLA) [47] ete. are applied. Most of the natural polymers exhibit high bioactivity and biocompatibility, how. ever, care must be taken to prevent denaturation during the scaffold preparation Inthe ease of synthetic polymers. Although ths problem is ‘minor in the case of synthetic polymers, particular attention has to Be paid to their biocompatibility. [Nano-hybrid bone tissue seaffold ean be fabricated by the in situ crystallization of HA in the polymer matrix through mixing of HA nane- partiles with the polymer matrix [18,21 31,33,35,48 49] or via HA synthesis inside che polymer mateix [20,50] as well a via 3D printing (3851-53) [At present theee-dimensional (SD) printing techniques attract @ agreat deal of interest asa promising tool to produce onalemand bone scaffolds for regenerative medieal applications (47,53-59]. This meth ad offers production of diverse and complex structures through computer-aided designs based on medical tests enabling visualization ofthe damaged tissue. 3D medical pricing technologies would make it possible to obtain personalized implants or grafts. It is known that composite materials containing polymer and ceramic constituents possess properties that are summation of bioactivity and mechanical stcength provided by the ceramie phase and biodegradability, tough- ness and flexibility originating from the polymer phase. Hence, many investigations have been cazried out to develop methods for 3D printing of polymer-ceramic compesites, of them polymer-hydroxyapatite com- posites are of great interest [17,55]. It was found both in vitro and/or in vivo tests that $D-printed bone sue engineering scaffolds, e.g, based on polycaprolactone (PCL)/HA (55,57), polylactide (PLA)/HA (47.53), ‘or poly(propylene fumarate) (PPF)/HA [58] enable bone healing, ‘Apart from their biocompatibility, such materials must also support cell viability, proliferation, and funetion. It i known that porous steveture provides adequate space which promotes bone ingrowth. Macropores facilitate osteoid formation and mineralization by increas ing the osteoblasts and osteoprogenitors migration into the scaffold, whereas interconnected micropores ean enhance vascularization and nutrient diffsion during bone reconstruction [47,55). Inks, which are used for biomaterial production, can be divided into two groups acellular and celhencapsulating [56]. The latter one in combination ‘withthe process carried out at room temperature allows incorporation of pharmaceutical and biological agents into scaffolds. The bone regeneration requires a source of mesenchymal stem cells that can differentiate into bone-forming esteoblasts (5S)Using the 8D printing method Liv et al (47] prepared the osteogenic, PLA/HA screwlike scalfold loaded with mesenchymal stem cells (482). The invite and in vivo tests showed thatthe PLA/HA scaffold Toaded with MSCs suspended! inthe Pluronic F-127 hydrogel promoted bone ingrowth and bone-graft interface formation inside the bone tunnel ‘ene in the coming future the 3D biomaterial printing technology ‘ill make a significant impact on orthopaedics, dental and oral surgery However, stil lot of efforts have tobe undertaken to satisfy the specific requisements, such ar structural, chemical, mechanical and biological In addition, such seafold can be loaded with drugs improving thee functionality (28,22,38]. Martinez-Vézquer et al. (38) obtained porous {3D seaffolds with good mechanical properties consisting of gelatin and Sidoped hydroxyapatite by rapid prototyping at room temperature, ‘whieh allowed also vancomycin incorporation. The gelatin presence ‘enhanced osteoblastic cell line MCST3-E1 differentiation and gene ‘expression, Vancomycin was released from the seaffoldgradually in the short term, effectively inhibiting bacterial growth around the material, Loper-Noriega et al. have shown (22) that the collagen= hydroxyapatite seaffolds withthe incorporated poly(lactic, Magee honest coatings sik oe aera say elon, ei od Dac thas) Singh Ak i Tl PateIKDMahaptra Dashing Kang MS, ta Now yd nnord ar of rect hyronyapae thle ah mesoporous anepransns, 1127) Detnba A, ea Dy Radia V, Pre MB, Sersa-Cindina L.Fuctonaand ‘ene draft ans nd nae) Lang ow VP, La Yo Ba 8 sae oan2s) (20 usu tus2) sn ee ass) 136) us ss) ss) tua) na uaa nas) an tuas) nae an as uss) nso) tus say tas se ss) tise) sn cate eos moore fr rg der ees we eh ‘Setiong tpt, RSC non aN Io Kola Guna pe are St Sus oan yee apteacwere peer obs nd ded spent Me ‘yeroayapatite/caligen seated coniining divloaded ADYHPLCA mee ‘Morr ve cer Cates] a see ave 70801 ‘erate sai ee nk ron ong be Ned, Dou) Yoo) Mestndi sn el alee ‘gto epg ges gy Sera i tt ta mpc oie Shao tats an at Yao prt des prs ca papa tower ir tl ei ney en 9 Mate S827 iNTRene Gas eA dae Wang), ao Yo ea ep a Eran of nae pn apap cnecebeae) pra Sphere torn cere ha Cen 21s 908 ‘ayant ac Dupes elvan 208 07850, Settee Yoninatt Tecmo ate Maven wee cost Siogepencnasen ‘Ning Saat ME Usd M.apbeponste ced Ipsos {Sin esto gen tyesep sets YP Sis cau shine R, ben Bere 8. Delp snd ‘tence one of hppa teat emesng hare Jehu wd bmp tow da ey nc Eng Rego Med Jone htp/7ectoary 0 looser 208 OX Bes CS tanya eal Osentge tot ned ‘jou Danse Vee Rema Mdan Maus Raton ‘nchydenopate Sad treme or eeprom, ae 580g © aatneaer Ope owe besos an ‘ic codebase Fe aeroplanes ot ‘cin Srsyoy spite sal Se 30118391690, Slows Serta Melina eter mowabe wpe cena, si Chow MDa PE Da a, Mada SK Mase bsson a het yom oa sree tite mechan yates Ca Pp 2017 90 Nien Nenscee haronepate bed eam 2 eos ea Sap ic Fron la an CM Mabe lS Sed rm ot Se cucarere nd vacuity byonapenepone oy noes Stescon terpn pope bye DoD) een ‘Sour cange rng tyr of eam per aero Si Seng ta, Gan thang Te arpa ene ok ‘None Ren as ng ¥, Sm Xt. Altered tyatiacoa bess of hres tance th enor Co sunhatnyph ieee eleoetaaas os mane? Ge et Nix che, Qn Yon, LC Caaiebo opherca Symp npn wing fer esis te Ha on etait, Neen TD, Pham A, col £0, Ayal. pes and Exist Subomanan Seti Vneti Seay Rc sae openaen of poe prs rin carn ‘ino sent res Nermape maser ing eso er 59 aso) be) usu tn62) os tose) st ass) nen toss) 0s) 1u70) un na 7s) ne 7s) tore) wn urs) 79) aso) us nas) ose) Atvancsin Clean Dac Seine 2482017) 821-830 ‘hydrgupite pecaer containing to capone spay page proces ot Chem Sel Eng 201480) 204-35. hos Lee 6 Rhee Si Ee of recne concnraon an pry pai leprae por hyenyapate parle siesta enity) Bomed Mar Ret ‘WaDkZ, X47, Zhaon W, Sab, A potential mechani for amine acd-onteled etl growth at hytoayapatie. ate Chea 82015591577 ‘Soi, kansnacs K Hatha 1 Opi fend pel erie pet ede Spopae eeprom Dg sak Bing cx, 2hu 9, QL ts BQ, Chen FW). Poo low mirepers of ‘crops ale phosphate eybees ii empled mucmave ste ‘here, ac. 1X Han i, Song Hower gamers of hydroyapae Cot frmed on sn egeshll membrane. Call Sot 2541 4090, isonet of bone Mi lg os {Contino mirawave fe ser mesporee heron, Mater Sl inde Dia 7,Deaa i, cio Monies ‘Wang 8, Guo 7 Rhembohedral hydroxyapatite with mesoporous achitecsre for Deepen vg ley. Chem at 2015447581 Nowsepeloe alr Hycreyapette caliente presees of nine ‘Geax Males J, Delgado Lopes JM, laisco M Hleraandes-tiesandes A Pak ‘Reve Inorg, Me-Org, Nano-Me Chee. 2075,45(3)411-8 "anes MOE Kair MRA, Svokr Ty Holekan A Sear MR, Naghicdh ‘umined Ne, Othman R, YEOH FY. Convaling he pore cacti aoismi@nioszss. ‘ol utc micles on hyeronypate anacytal omatos snes {ation iat the nresi-ogni terol cans, CH Growth Der Sapp Wibo 9, Shee K arya Fale fs X10 and hye tt nen ae ef prs yao ae Stier asens Nuun! tong, 8TH, So YL Singh D Ha SS Haband ell ihley ‘i hydrnsapate anos by vaacant mead sates negro ‘how arg Melos, Deng Menports hydro spa anoperies Eyer stn esis wh human te ‘Rordwka A. Sucees A. Syethess of nove sitea/apatte wresoperts narecon pte ate Lat 201065275-8 Tio 5, Chach 2G, Wang 1. hcepberes of byronypalile rected UskokoweV, Dent TA In vito analy of nanoparseaate hydroxyapatite? ‘itauancomportes pote! ag dlery piv foc the rated lea ‘Nez Su), WuQ, Yang Co lion ydsnyapeie peeled ‘Nellore J, Vieyaabst$, Priyanka P, Priyadarsbln. Preparation and inital $iecrsatbity eatin of blgenc hyenas choran/pvy ee Res oisschses-s. behavior of neve! bioplyes/yéroryaptce nanocomposite Deeds, Asan Joe tase, nes) i901 a usa svadied hy droxyapate nanopaicles for bone-apecite al delivery of dg and Denese Maron! Hes 20262807) 85-8 ‘abn Shimoda. SopareK Ogom Uy Seizawe , Abs M- ‘Sisamat, Pad Watanabe Jal Yor, Neaoo ea Renee Dekaron coon Doe ena a Tisag £0, Pang chen 22 Tan XP. Deabesvery ef asco and cara ection an pron bone healing, Ml Med Rep 20112217, Gu ek wd Masons Fe Opto ogee fr ated ug Pinon Ansan D,Pnse 8 Monat M, Tampies A, Galeagoe ptr nagoete WENT taneeamponte wa bnconpable shi aos) 9 ta9s) tn96) Avene Cd andere Sie 249 (2017 321-830 ‘rain sla Ka AP Pra AL Ge Sata ‘Ba Kann Sas et opto ‘Wao YC T Keng Gi W, Te, Zhu Y, bao H Magnte lamellar ‘poy asta ey 2 er ann sna a ng 15% nC a dep