fcmedicineФундаментальная и клиническая медицинаFundamental and Clinical Medicine2500-07642542-0941КемГМУ10.23946/2500-0764-2021-6-1-16-26fcmedicine-368Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL RESEARCHИспользование ксеногенного нативного костного минерала для замещения критических костных дефектов свода черепа крысXenogeneic bone mineral is efficient for the repair of critical-sized rat calvarial defectshttps://orcid.org/0000-0001-9946-1015ВеремеевА. В.VeremeevA. V.

Веремеев Алексей Владимирович, кандидат медицинских наук, генеральный директор ООО «Матрифлекс»

125252, г. Москва, ул. Авиаконструктора Микояна, д. 12, корп. А, п. 1, эт. 2, оф. 1

Alexey V. Veremeev, Dr., MD, PhD, Chief Executive Offcer, Matrifex LLC

12А, Aviakonstruktora Mikoyana Street, Moscow, 125252

al.veremeev@gmail.comhttps://orcid.org/0000-0001-8679-4857БолгаринР. Н.BolgarinR. N.

Болгарин Роман Николаевич, директор по развитию

125252, г. Москва, ул. Авиаконструктора Микояна, д. 12, корп. А, п. 1, эт. 2, оф. 1

Roman N. Bolgarin, Mr., Development Director

12А, Aviakonstruktora Mikoyana Street, Moscow, 125252

https://orcid.org/0000-0001-5623-2466НестеренкоВ. Г.NesterenkoV. G.

Нестеренко Владимир Георгиевич, доктор медицинских наук, профессор, заведующий отделом иммунологии

123098, г. Москва, ул. Гамалеи, д. 18

Vladimir G. Nesterenko, Prof., MD, DSc, Professor, Head of the Immunology Department

18, Gamaleya Street, Moscow, 123098

https://orcid.org/0000-0002-1173-8153Андреев-АндриевскийА. А.Andreev-AndrievskiyA. A.

Андреев-Андриевский Александр Александрович, кандидат биологических наук, руководитель центра доклинических исследований ООО «НИИ митоинженерии МГУ»

119330, г. Москва, ул. Ленинские горы, д. 73А

Alexander A. Andreev-Andrievskiy, Dr., PhD, Head of the Center for Preclinical Trials, Mitoengineering Research Institute LLC, Moscow State University

73A, Leninskie Gory Street, Moscow, 119330

Общество с ограниченной ответственностью «Матрифлекс»; ФГБУ «Национальный исследовательский центр эпидемиологии и микробиологии имени почётного академика Н. Ф. Гамалеи» Министерства здравоохранения Российской ФедерацииРоссияMatrifex LLC; Gamaleya National Research Centre of Epidemiology and MicrobiologyRussian FederationОбщество с ограниченной ответственностью «Матрифлекс»РоссияMatrifex LLCRussian FederationФГБУ «Национальный исследовательский центр эпидемиологии и микробиологии имени почётного академика Н. Ф. Гамалеи» Министерства здравоохранения Российской ФедерацииРоссияGamaleya National Research Centre of Epidemiology and MicrobiologyRussian FederationМосковский государственный университет имени М.В. ЛомоносоваРоссияMoscow State UniversityRussian Federation202128032021611626Copyright © Веремеев А.В., Болгарин Р.Н., Нестеренко В.Г., Андреев-Андриевский А.А., 20212021Веремеев А.В., Болгарин Р.Н., Нестеренко В.Г., Андреев-Андриевский А.А.Veremeev A.V., Bolgarin R.N., Nesterenko V.G., Andreev-Andrievskiy A.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://fcm.kemsmu.ru/jour/article/view/368Цель

Цель. Оценить эффективность замещения дефектов костной ткани у крыс оригинальным ксеногенным нативным минералом в сравнении с широко распространенным нативным костным минералом Geistlich Bio-Oss® и аутотрансплантатом.

Материалы и методы

Материалы и методы. Крысам SpragueDawley (n = 48) искусственно создавали критический дефект путем трепанации свода черепа. Животных подразделяли на 4 группы (n = 12). В первой группе дефект оставляли незаполненным (отрицательный контроль), во второй замещали аутотрансплантатом (положительный контроль), в третьей – препаратом-компаратором Geistlich Bio-Oss и в четвертой – тестируемым ксеногенным нативным минералом. Вывод крыс из эксперимента производили через 4 и 12 месяцев (по 6 крыс из каждой группы на временную точку). Биоптаты включали в себя область дефекта и прилежащие нативные ткани. Методом микрокомпьютерного томографирования моделировали трехмерную структуру, определяли степень минерализации ткани и измеряли объем новообразованных костных элементов. Для исследования микроструктуры костных биоптатов ткань подвергали декальцинированию в электролитном растворе в течение 96 часов, затем окрашивали гематоксилином и эозином.

Результаты

Результаты. Наибольший объем новообразованной костной ткани наблюдали у крыс положительного контроля, наименьший – у крыс отрицательного контроля. У крыс, которым костный дефект замещали оригинальным ксеногенным костным минералом, объем новообразованной ткани был выше, чем в группе особей с замещением костного дефекта препаратом-компаратором Geistlich Bio-Oss. Показатели минеральной плотности, толщины костных балок и доли минерализации между экспериментальными группами не отличались и находились ближе к показателям группы положительного контроля, что свидетельствует об их эффективности.

Заключение

Заключение. Оригинальный ксеногенный костный минерал способствует индукции регенерации костной ткани по сравнению с широко используемым в клинической практике препаратом Geistlich Bio-Oss®.

Aim

Aim. To evaluate the efficiency of bone repair on a critical-sized rat calvarial defect model using our original xenogeneic bone mineral, widely established Geistlich Bio-Oss®, and autologous bone graft.

Materials and Methods

Materials and Methods. We created a critical-sized calvarial defect in Sprague-Dawley rats (n = 48) and then divided them into 4 groups (unfilled defect, autologous bone graft, Geistlich BioOss® and our original xenogeneic bone mineral, 12 rats per group). Rats were sacrificed upon 4 and 12 months (6 rats per time point) with the following excision of the implant and adjacent tissues. 3D structure, extent of mineralisation, and bone volume were measured by means of microcomputed tomography. Microanatomy of the explants and adjacent tissue was investigated by haematoxylin and eosin staining.

Results

Results. The highest and the lowest bone volume was expectedly detected when the defect was filled with the autologous bone graft or remained unfilled, respectively. Replacement of the defect by the original bone mineral entailed better regeneration as compared to Geistlich Bio-Oss. Bone mineral density, bone thickness and the extent of mineralisation did not differ significantly between the experimental groups and were close to the positive control values, indicating efficient bone repair.

Conclusions

Conclusions. Original xenogeneic bone mineral promotes induction of bone regeneration as compared to Geistlich Bio-Oss®, a commercially available bone mineral widely used in the clinical practice.

ксеногенный костный минералминерализациякостный трансплантатпатологии опорно-двигательного аппаратxenogeneic bone mineralmineralisationbone transplantmusculoskeletal disordersReferencesCourney P Maxwell, ed. Recent Advances in Orthopedics-2. Jaypee Brothers Medical Publishers; 2018.Courney P Maxwell, ed. Recent Advances in Orthopedics-2. Jaypee Brothers Medical Publishers; 2018.GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211-1259. https://doi.org/10.1016/S0140-6736(17)32154-2GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211-1259. https://doi.org/10.1016/S0140-6736(17)32154-2Haagsma JA, Graetz N, Bolliger I, Naghavi M, Higashi H, Mullany EC, Abera SF, Abraham JP, Adofo K, Alsharif U, Ameh EA, Ammar W, Antonio CA, Barrero LH, Bekele T, Bose D, Brazinova A, Catalá-López F, Dandona L, Dandona R, Dargan PI, De Leo D, Degenhardt L, Derrett S, Dharmaratne SD, Driscoll TR, Duan L, Petrovich Ermakov S, Farzadfar F, Feigin VL, Franklin RC, Gabbe B, Gosselin RA, Hafezi-Nejad N, Hamadeh RR, Hijar M, Hu G, Jayaraman SP, Jiang G, Khader YS, Khan EA, Krishnaswami S, Kulkarni C, Lecky FE, Leung R, Lunevicius R, Lyons RA, Majdan M, Mason-Jones AJ, Matzopoulos R, Meaney PA, Mekonnen W, Miller TR, Mock CN, Norman RE, Orozco R, Polinder S, Pourmalek F, Rahimi-Movaghar V, Refaat A, Rojas-Rueda D, Roy N, Schwebel DC, Shaheen A, Shahraz S, Skirbekk V, Søreide K, Soshnikov S, Stein DJ, Sykes BL, Tabb KM, Temesgen AM, Tenkorang EY, Theadom AM, Tran BX, Vasankari TJ, Vavilala MS, Vlassov VV, Woldeyohannes SM, Yip P, Yonemoto N, Younis MZ, Yu C, Murray CJ, Vos T. The global burden of injury: incidence, mortality, disability-adjusted life years and time trends from the Global Burden of Disease study 2013. Inj Prev. 2016;22(1):3-18. https://doi.org/10.1136/injuryprev-2015-041616Haagsma JA, Graetz N, Bolliger I, Naghavi M, Higashi H, Mullany EC, Abera SF, Abraham JP, Adofo K, Alsharif U, Ameh EA, Ammar W, Antonio CA, Barrero LH, Bekele T, Bose D, Brazinova A, Catalá-López F, Dandona L, Dandona R, Dargan PI, De Leo D, Degenhardt L, Derrett S, Dharmaratne SD, Driscoll TR, Duan L, Petrovich Ermakov S, Farzadfar F, Feigin VL, Franklin RC, Gabbe B, Gosselin RA, Hafezi-Nejad N, Hamadeh RR, Hijar M, Hu G, Jayaraman SP, Jiang G, Khader YS, Khan EA, Krishnaswami S, Kulkarni C, Lecky FE, Leung R, Lunevicius R, Lyons RA, Majdan M, Mason-Jones AJ, Matzopoulos R, Meaney PA, Mekonnen W, Miller TR, Mock CN, Norman RE, Orozco R, Polinder S, Pourmalek F, Rahimi-Movaghar V, Refaat A, Rojas-Rueda D, Roy N, Schwebel DC, Shaheen A, Shahraz S, Skirbekk V, Søreide K, Soshnikov S, Stein DJ, Sykes BL, Tabb KM, Temesgen AM, Tenkorang EY, Theadom AM, Tran BX, Vasankari TJ, Vavilala MS, Vlassov VV, Woldeyohannes SM, Yip P, Yonemoto N, Younis MZ, Yu C, Murray CJ, Vos T. The global burden of injury: incidence, mortality, disability-adjusted life years and time trends from the Global Burden of Disease study 2013. Inj Prev. 2016;22(1):3-18. https://doi.org/10.1136/injuryprev-2015-041616Global Burden of Disease Child and Adolescent Health Collaboration, Kassebaum N, Kyu HH, Zoeckler L, Olsen HE, Thomas K, Pinho C, Bhutta ZA, Dandona L, Ferrari A, Ghiwot TT, Hay SI, Kinfu Y, Liang X, Lopez A, Malta DC, Mokdad AH, Naghavi M, Patton GC, Salomon J, Sartorius B, Topor-Madry R, Vollset SE, Werdecker A, Whiteford HA, Abate KH, Abbas K, Damtew SA, Ahmed MB, Akseer N, Al-Raddadi R, Alemayohu MA, Altirkawi K, Abajobir AA, Amare AT, Antonio CAT, Arnlov J, Artaman A, Asayesh H, Avokpaho EFGA, Awasthi A, Ayala Quintanilla BP, Bacha U, Betsu BD, Barac A, Bärnighausen TW, Baye E, Bedi N, Bensenor IM, Berhane A, Bernabe E, Bernal OA, Beyene AS, Biadgilign S, Bikbov B, Boyce CA, Brazinova A, Hailu GB, Carter A, Castañeda-Orjuela CA, Catalá-López F, Charlson FJ, Chitheer AA, Choi JJ, Ciobanu LG, Crump J, Dandona R, Dellavalle RP, Deribew A, deVeber G, Dicker D, Ding EL, Dubey M, Endries AY, Erskine HE, Faraon EJA, Faro A, Farzadfar F, Fernandes JC, Fijabi DO, Fitzmaurice C, Fleming TD, Flor LS, Foreman KJ, Franklin RC, Fraser MS, Frostad JJ, Fullman N, Gebregergs GB, Gebru AA, Geleijnse JM, Gibney KB, Gidey Yihdego M, Ginawi IAM, Gishu MD, Gizachew TA, Glaser E, Gold AL, Goldberg E, Gona P, Goto A, Gugnani HC, Jiang G, Gupta R, Tesfay FH, Hankey GJ, Havmoeller R, Hijar M, Horino M, Hosgood HD, Hu G, Jacobsen KH, Jakovljevic MB, Jayaraman SP, Jha V, Jibat T, Johnson CO, Jonas J, Kasaeian A, Kawakami N, Keiyoro PN, Khalil I, Khang YH, Khubchandani J, Ahmad Kiadaliri AA, Kieling C, Kim D, Kissoon N, Knibbs LD, Koyanagi A, Krohn KJ, Kuate Defo B, Kucuk Bicer B, Kulikoff R, Kumar GA, Lal DK, Lam HY, Larson HJ, Larsson A, Laryea DO, Leung J, Lim SS, Lo LT, Lo WD, Looker KJ, Lotufo PA, Magdy Abd El Razek H, Malekzadeh R, Markos Shifti D, Mazidi M, Meaney PA, Meles KG, Memiah P, Mendoza W, Abera Mengistie M, Mengistu GW, Mensah GA, Miller TR, Mock C, Mohammadi A, Mohammed S, Monasta L, Mueller U, Nagata C, Naheed A, Nguyen G, Nguyen QL, Nsoesie E, Oh IH, Okoro A, Olusanya JO, Olusanya BO, Ortiz A, Paudel D, Pereira DM, Perico N, Petzold M, Phillips MR, Polanczyk GV, Pourmalek F, Qorbani M, Rafay A, Rahimi-Movaghar V, Rahman M, Rai RK, Ram U, Rankin Z, Remuzzi G, Renzaho AMN, Roba HS, Rojas-Rueda D, Ronfani L, Sagar R, Sanabria JR, Kedir Mohammed MS, Santos IS, Satpathy M, Sawhney M, Schöttker B, Schwebel DC, Scott JG, Sepanlou SG, Shaheen A, Shaikh MA, She J, Shiri R, Shiue I, Sigfusdottir ID, Singh J, Silpakit N, Smith A, Sreeramareddy C, Stanaway JD, Stein DJ, Steiner C, Sufyan MB, Swaminathan S, Tabarés-Seisdedos R, Tabb KM, Tadese F, Tavakkoli M, Taye B, Teeple S, Tegegne TK, Temam Shifa G, Terkawi AS, Thomas B, Thomson AJ, TobeGai R, Tonelli M, Tran BX, Troeger C, Ukwaja KN, Uthman O, Vasankari T, Venketasubramanian N, Vlassov VV, Weiderpass E, Weintraub R, Gebrehiwot SW, Westerman R, Williams HC, Wolfe CDA, Woodbrook R, Yano Y, Yonemoto N, Yoon SJ, Younis MZ, Yu C, Zaki MES, Zegeye EA, Zuhlke LJ, Murray CJL, Vos T. Child and Adolescent Health From 1990 to 2015: Findings From the Global Burden of Diseases, Injuries, and Risk Factors 2015 Study. JAMA Pediatr. 2017;171(6):573-592. https://doi.org/10.1001/jamapediatrics.2017.0250Global Burden of Disease Child and Adolescent Health Collaboration, Kassebaum N, Kyu HH, Zoeckler L, Olsen HE, Thomas K, Pinho C, Bhutta ZA, Dandona L, Ferrari A, Ghiwot TT, Hay SI, Kinfu Y, Liang X, Lopez A, Malta DC, Mokdad AH, Naghavi M, Patton GC, Salomon J, Sartorius B, Topor-Madry R, Vollset SE, Werdecker A, Whiteford HA, Abate KH, Abbas K, Damtew SA, Ahmed MB, Akseer N, Al-Raddadi R, Alemayohu MA, Altirkawi K, Abajobir AA, Amare AT, Antonio CAT, Arnlov J, Artaman A, Asayesh H, Avokpaho EFGA, Awasthi A, Ayala Quintanilla BP, Bacha U, Betsu BD, Barac A, Bärnighausen TW, Baye E, Bedi N, Bensenor IM, Berhane A, Bernabe E, Bernal OA, Beyene AS, Biadgilign S, Bikbov B, Boyce CA, Brazinova A, Hailu GB, Carter A, Castañeda-Orjuela CA, Catalá-López F, Charlson FJ, Chitheer AA, Choi JJ, Ciobanu LG, Crump J, Dandona R, Dellavalle RP, Deribew A, deVeber G, Dicker D, Ding EL, Dubey M, Endries AY, Erskine HE, Faraon EJA, Faro A, Farzadfar F, Fernandes JC, Fijabi DO, Fitzmaurice C, Fleming TD, Flor LS, Foreman KJ, Franklin RC, Fraser MS, Frostad JJ, Fullman N, Gebregergs GB, Gebru AA, Geleijnse JM, Gibney KB, Gidey Yihdego M, Ginawi IAM, Gishu MD, Gizachew TA, Glaser E, Gold AL, Goldberg E, Gona P, Goto A, Gugnani HC, Jiang G, Gupta R, Tesfay FH, Hankey GJ, Havmoeller R, Hijar M, Horino M, Hosgood HD, Hu G, Jacobsen KH, Jakovljevic MB, Jayaraman SP, Jha V, Jibat T, Johnson CO, Jonas J, Kasaeian A, Kawakami N, Keiyoro PN, Khalil I, Khang YH, Khubchandani J, Ahmad Kiadaliri AA, Kieling C, Kim D, Kissoon N, Knibbs LD, Koyanagi A, Krohn KJ, Kuate Defo B, Kucuk Bicer B, Kulikoff R, Kumar GA, Lal DK, Lam HY, Larson HJ, Larsson A, Laryea DO, Leung J, Lim SS, Lo LT, Lo WD, Looker KJ, Lotufo PA, Magdy Abd El Razek H, Malekzadeh R, Markos Shifti D, Mazidi M, Meaney PA, Meles KG, Memiah P, Mendoza W, Abera Mengistie M, Mengistu GW, Mensah GA, Miller TR, Mock C, Mohammadi A, Mohammed S, Monasta L, Mueller U, Nagata C, Naheed A, Nguyen G, Nguyen QL, Nsoesie E, Oh IH, Okoro A, Olusanya JO, Olusanya BO, Ortiz A, Paudel D, Pereira DM, Perico N, Petzold M, Phillips MR, Polanczyk GV, Pourmalek F, Qorbani M, Rafay A, Rahimi-Movaghar V, Rahman M, Rai RK, Ram U, Rankin Z, Remuzzi G, Renzaho AMN, Roba HS, Rojas-Rueda D, Ronfani L, Sagar R, Sanabria JR, Kedir Mohammed MS, Santos IS, Satpathy M, Sawhney M, Schöttker B, Schwebel DC, Scott JG, Sepanlou SG, Shaheen A, Shaikh MA, She J, Shiri R, Shiue I, Sigfusdottir ID, Singh J, Silpakit N, Smith A, Sreeramareddy C, Stanaway JD, Stein DJ, Steiner C, Sufyan MB, Swaminathan S, Tabarés-Seisdedos R, Tabb KM, Tadese F, Tavakkoli M, Taye B, Teeple S, Tegegne TK, Temam Shifa G, Terkawi AS, Thomas B, Thomson AJ, TobeGai R, Tonelli M, Tran BX, Troeger C, Ukwaja KN, Uthman O, Vasankari T, Venketasubramanian N, Vlassov VV, Weiderpass E, Weintraub R, Gebrehiwot SW, Westerman R, Williams HC, Wolfe CDA, Woodbrook R, Yano Y, Yonemoto N, Yoon SJ, Younis MZ, Yu C, Zaki MES, Zegeye EA, Zuhlke LJ, Murray CJL, Vos T. Child and Adolescent Health From 1990 to 2015: Findings From the Global Burden of Diseases, Injuries, and Risk Factors 2015 Study. JAMA Pediatr. 2017;171(6):573-592. https://doi.org/10.1001/jamapediatrics.2017.0250Mokdad AH, Forouzanfar MH, Daoud F, Mokdad AA, El Bcheraoui C, Moradi-Lakeh M, Kyu HH, Barber RM, Wagner J, Cercy K, Kravitz H, Coggeshall M, Chew A, O'Rourke KF, Steiner C, Tuffaha M, Charara R, Al-Ghamdi EA, Adi Y, Aff RA, Alahmadi H, AlBuhairan F, Allen N, AlMazroa M, Al-Nehmi AA, AlRayess Z, Arora M, Azzopardi P, Barroso C, Basulaiman M, Bhutta ZA, Bonell C, Breinbauer C, Degenhardt L, Denno D, Fang J, Fatusi A, Feigl AB, Kakuma R, Karam N, Kennedy E, Khoja TA, Maalouf F, Obermeyer CM, Mattoo A, McGovern T, Memish ZA, Mensah GA, Patel V, Petroni S, Reavley N, Zertuche DR, Saeedi M, Santelli J, Sawyer SM, Ssewamala F, Taiwo K, Tantawy M, Viner RM, Waldfogel J, Zuñiga MP, Naghavi M, Wang H, Vos T, Lopez AD, Al Rabeeah AA, Patton GC, Murray CJ. Global burden of diseases, injuries, and risk factors for young people's health during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2016;387(10036):2383-2401. https://doi.org/10.1016/S0140-6736(16)00648-6Mokdad AH, Forouzanfar MH, Daoud F, Mokdad AA, El Bcheraoui C, Moradi-Lakeh M, Kyu HH, Barber RM, Wagner J, Cercy K, Kravitz H, Coggeshall M, Chew A, O'Rourke KF, Steiner C, Tuffaha M, Charara R, Al-Ghamdi EA, Adi Y, Aff RA, Alahmadi H, AlBuhairan F, Allen N, AlMazroa M, Al-Nehmi AA, AlRayess Z, Arora M, Azzopardi P, Barroso C, Basulaiman M, Bhutta ZA, Bonell C, Breinbauer C, Degenhardt L, Denno D, Fang J, Fatusi A, Feigl AB, Kakuma R, Karam N, Kennedy E, Khoja TA, Maalouf F, Obermeyer CM, Mattoo A, McGovern T, Memish ZA, Mensah GA, Patel V, Petroni S, Reavley N, Zertuche DR, Saeedi M, Santelli J, Sawyer SM, Ssewamala F, Taiwo K, Tantawy M, Viner RM, Waldfogel J, Zuñiga MP, Naghavi M, Wang H, Vos T, Lopez AD, Al Rabeeah AA, Patton GC, Murray CJ. Global burden of diseases, injuries, and risk factors for young people's health during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2016;387(10036):2383-2401. https://doi.org/10.1016/S0140-6736(16)00648-6Hasan A, Byambaa B, Morshed M, Cheikh MI, Shakoor RA, Mus tafy T, Marei H. Advances in osteobiologic materials for bone substitutes. J Tissue Eng Regen Med. 2018;12(6):1448-1468. https://doi.org/10.1002/term.2677Hasan A, Byambaa B, Morshed M, Cheikh MI, Shakoor RA, Mus tafy T, Marei H. Advances in osteobiologic materials for bone substitutes. J Tissue Eng Regen Med. 2018;12(6):1448-1468. https://doi.org/10.1002/term.2677Pearlin, Nayak S, Manivasagam G, Sen D. Progress of Regenerative Therapy in Orthopedics. Curr Osteoporos Rep. 2018;16(2):169- 181. https://doi.org/10.1007/s11914-018-0428-xPearlin, Nayak S, Manivasagam G, Sen D. Progress of Regenerative Therapy in Orthopedics. Curr Osteoporos Rep. 2018;16(2):169- 181. https://doi.org/10.1007/s11914-018-0428-xSmith WR, Hudson PW, Ponce BA, Rajaram Manoharan SR. Nanotechnology in orthopedics: a clinically oriented review. BMC Musculoskelet Disord. 2018;19(1):67. https://doi.org/10.1186/s12891-018-1990-1Smith WR, Hudson PW, Ponce BA, Rajaram Manoharan SR. Nanotechnology in orthopedics: a clinically oriented review. BMC Musculoskelet Disord. 2018;19(1):67. https://doi.org/10.1186/s12891-018-1990-1Azi ML, Aprato A, Santi I, Kfuri M Jr, Masse A, Joeris A. Autologous bone graft in the treatment of post-traumatic bone defects: a systematic review and meta-analysis. BMC Musculoskelet Disord. 2016;17(1):465. https://doi.org/10.1186/s12891-016-1312-4Azi ML, Aprato A, Santi I, Kfuri M Jr, Masse A, Joeris A. Autologous bone graft in the treatment of post-traumatic bone defects: a systematic review and meta-analysis. BMC Musculoskelet Disord. 2016;17(1):465. https://doi.org/10.1186/s12891-016-1312-4Fillingham Y, Jacobs J. Bone grafts and their substitutes. Bone Joint J. 2016;98-B(1 Suppl A):6-9. https://doi.org/10.1302/0301-620X.98B.36350Fillingham Y, Jacobs J. Bone grafts and their substitutes. Bone Joint J. 2016;98-B(1 Suppl A):6-9. https://doi.org/10.1302/0301-620X.98B.36350Bhatt RA, Rozental TD. Bone graft substitutes. Hand Clin. 2012;28(4):457-68. https://doi.org/10.1016/j.hcl.2012.08.001Bhatt RA, Rozental TD. Bone graft substitutes. Hand Clin. 2012;28(4):457-68. https://doi.org/10.1016/j.hcl.2012.08.001Roberts TT, Rosenbaum AJ. Bone grafts, bone substitutes and orthobiologics: the bridge between basic science and clinical advancements in fracture healing. Organogenesis 2012;8:114-124. https://doi.org/10.4161/org.23306Roberts TT, Rosenbaum AJ. Bone grafts, bone substitutes and orthobiologics: the bridge between basic science and clinical advancements in fracture healing. Organogenesis 2012;8:114-124. https://doi.org/10.4161/org.23306Boskey AL. Bone composition: relationship to bone fragility and antiosteoporotic drug effects. Bonekey Rep. 2013;2:447. https://doi.org/10.1038/bonekey.2013.181Boskey AL. Bone composition: relationship to bone fragility and antiosteoporotic drug effects. Bonekey Rep. 2013;2:447. https://doi.org/10.1038/bonekey.2013.181Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol. 2008;3 Suppl 3(Suppl 3):S131-9. https://doi.org/10.2215/CJN.04151206Clarke B. Normal bone anatomy and physiology. Clin J Am Soc Nephrol. 2008;3 Suppl 3(Suppl 3):S131-9. https://doi.org/10.2215/CJN.04151206Bagher Z, Rajaei F, Shokrgozar M. Comparative study of bone repair using porous hydroxyapatite/ β-tricalcium phosphate and xenograft scaffold in rabbits with tibia defect. Iran Biomed J. 2012;16(1):18- 24. https://doi.org/10.6091/IBJ.996.2012Bagher Z, Rajaei F, Shokrgozar M. Comparative study of bone repair using porous hydroxyapatite/ β-tricalcium phosphate and xenograft scaffold in rabbits with tibia defect. Iran Biomed J. 2012;16(1):18- 24. https://doi.org/10.6091/IBJ.996.2012Li Q, Zhou G, Yu X, Wang T, Xi Y, Tang Z. Porous deproteinized bovine bone scaffold with three-dimensional localized drug delivery system using chitosan microspheres. Biomed Eng Online. 2015;14:33. https://doi.org/10.1186/s12938-015-0028-2Li Q, Zhou G, Yu X, Wang T, Xi Y, Tang Z. Porous deproteinized bovine bone scaffold with three-dimensional localized drug delivery system using chitosan microspheres. Biomed Eng Online. 2015;14:33. https://doi.org/10.1186/s12938-015-0028-2Kurkcu M, Benlidayi ME, Cam B, Sertdemir Y. Anorganic bovine-derived hydroxyapatite vs β-tricalcium phosphate in sinus augmentation: a comparative histomorphometric study. J Oral Implantol. 2012;38:519-26. https://doi.org/10.1563/AAIDJOI-D-11-00061Kurkcu M, Benlidayi ME, Cam B, Sertdemir Y. Anorganic bovine-derived hydroxyapatite vs β-tricalcium phosphate in sinus augmentation: a comparative histomorphometric study. J Oral Implantol. 2012;38:519-26. https://doi.org/10.1563/AAIDJOI-D-11-00061Salgado CL, Grenho L, Fernandes MH, Colaço BJ, Monteiro FJ. Biodegradation, biocompatibility, and osteoconduction evaluation of collagen-nanohydroxyapatite cryogels for bone tissue regeneration. J Biomed Mater Res A. 2016;104(1):57-70. https://doi.org/10.1002/jbm.a.35540Salgado CL, Grenho L, Fernandes MH, Colaço BJ, Monteiro FJ. Biodegradation, biocompatibility, and osteoconduction evaluation of collagen-nanohydroxyapatite cryogels for bone tissue regeneration. J Biomed Mater Res A. 2016;104(1):57-70. https://doi.org/10.1002/jbm.a.35540Cha JK, Lee JS, Kim MS, Choi SH, Cho KS, Jung UW. Sinus augmentation using BMP-2 in a bovine hydroxyapatite/collagen carrier in dogs. J Clin Periodontol. 2014;41(1):86-93. https://doi.org/10.1111/jcpe.12174Cha JK, Lee JS, Kim MS, Choi SH, Cho KS, Jung UW. Sinus augmentation using BMP-2 in a bovine hydroxyapatite/collagen carrier in dogs. J Clin Periodontol. 2014;41(1):86-93. https://doi.org/10.1111/jcpe.12174Lü X, Wang J, Li B, Zhang Z, Zhao L. Gene expression profle study on osteoinductive effect of natural hydroxyapatite. J Biomed Mater Res A. 2014;102(8):2833-41. https://doi.org/10.1002/jbm.a.34951Lü X, Wang J, Li B, Zhang Z, Zhao L. Gene expression profle study on osteoinductive effect of natural hydroxyapatite. J Biomed Mater Res A. 2014;102(8):2833-41. https://doi.org/10.1002/jbm.a.34951Spicer PP, Kretlow JD, Young S, Jansen JA, Kasper FK, Mikos AG. Evaluation of bone regeneration using the rat critical size calvarial defect. Nat Protoc. 2012;7(10):1918-29. https://doi.org/10.1038/nprot.2012.113Spicer PP, Kretlow JD, Young S, Jansen JA, Kasper FK, Mikos AG. Evaluation of bone regeneration using the rat critical size calvarial defect. Nat Protoc. 2012;7(10):1918-29. https://doi.org/10.1038/nprot.2012.113Brydone AS, Meek D, Maclaine S. Bone grafting, orthopaedic biomaterials, and the clinical need for bone engineering. Proc Inst Mech Eng H. 2010;224(12):1329-43. https://doi.org/10.1243/09544119JEIM770Brydone AS, Meek D, Maclaine S. Bone grafting, orthopaedic biomaterials, and the clinical need for bone engineering. Proc Inst Mech Eng H. 2010;224(12):1329-43. https://doi.org/10.1243/09544119JEIM770O'Keefe RJ, Mao J. Bone tissue engineering and regeneration: from discovery to the clinic--an overview. Tissue Eng Part B Rev. 2011;17(6):389-92. https://doi.org/10.1089/ten.TEB.2011.0475O'Keefe RJ, Mao J. Bone tissue engineering and regeneration: from discovery to the clinic--an overview. Tissue Eng Part B Rev. 2011;17(6):389-92. https://doi.org/10.1089/ten.TEB.2011.0475

The authors declare that there are no conflicts of interest present.