生物源性钙磷灰石尺寸引发的骨仿生层级演变及其骨凝血免疫效应

doi:10.7518/hxkq.2024.2024315

华西口腔医学杂志 ›› 2024, Vol. 42 ›› Issue (6): 706-715.doi: 10.7518/hxkq.2024.2024315

生物源性钙磷灰石尺寸引发的骨仿生层级演变及其骨凝血免疫效应

许洁芸(), 赵原(), 刘浩州, 尹靖元, 陈泽涛()

中山大学附属口腔医院，广东省口腔医学重点实验室，广州 510055

收稿日期:2024-08-26 修回日期:2024-09-30 出版日期:2024-12-01 发布日期:2024-11-29
通讯作者: 陈泽涛 E-mail:xujy273@mail.sysu.edu.cn;zhaoy585@mail2.sysu.edu.cn;chenzet3@mail.sysu.edu.cn
作者简介:许洁芸，助理研究员，博士，E-mail：xujy273@mail.sysu.edu.cn|赵原，硕士，E-mail：zhaoy585@mail2.sysu.edu.cn
基金资助:
广东省科技计划项目(2023A0505050138);国家自然科学基金面上项目(82071167);广州市科技计划项目(2024A04-J6323);国家资助博士后研究人员计划(GZC20233280)

Hierarchical evolution of bone biomimicry and osteo-coagulo-immunomodulation induced by the size of biological hydroxyapatite

Xu Jieyun(), Zhao Yuan(), Liu Haozhou, Yin Jingyuan, Chen Zetao()

Hospital of Stomatology, Sun Yat-sen University & Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China

Received:2024-08-26 Revised:2024-09-30 Online:2024-12-01 Published:2024-11-29
Contact: Chen Zetao E-mail:xujy273@mail.sysu.edu.cn;zhaoy585@mail2.sysu.edu.cn;chenzet3@mail.sysu.edu.cn
Supported by:
Guangdong Province Scientific and Technological Funds(2023A0505050138);National Natural Science Foundation of China(82071167);Science and Technology Program of Guangzhou(2024A04J6323);Postdoctoral Fellowship Program of China Postdoctoral Science Foundation(GZC20233280)

摘要/Abstract

摘要：

生物源性钙磷灰石（BHA）因良好的生物相容性和骨传导性，广泛应用于临床骨缺损的治疗中。基于临床应用中的骨缺损区适配原则，BHA具有尺寸多元性设计，然而不同尺寸对应着不同的骨仿生层级，随着尺寸变化，其具备的骨仿生层级随之演变，并通过骨凝血免疫调控影响骨修复再生进程，导致植骨结局不稳定。本文对BHA的尺寸效应进行回顾，通过分析天然骨多级结构，提出BHA尺寸引发骨仿生层级演变，仿生层级介导凝血免疫效应，并基于骨仿生层级及其骨凝血免疫效应，提出对不同尺寸BHA材料生物学效应的新认识及其生物学原理，为不同尺寸BHA材料的基础研发和临床应用提供理论基础。

关键词: 生物源性钙磷灰石, 仿生层级演变, 骨凝血免疫, 材料尺寸效应

Abstract:

Biological hydroxyapatite (BHA) is widely used in the treatment of clinical bone defects due to its good biocompatibility and osteoconductivity. The clinical application of mateiral size is based on the principle of bone defect area adaptation, which contributes to diversity of BHA sizes. However, different sizes correspond to different hierarchical levels of bone biomimicry. As the size changes, the bone biomimicry hierarchy evolves accordingly and influences the process of bone repair and regeneration through osteo-coagulo-immunomodulation, leading to unstable bone graft outcomes. Therefore, this paper reviews the size effect of clinical BHA, analyzes the multilevel structure of natural bone, proposes the evolution of bone biomimetic hierarchy triggered by the size of BHA, and further analyzes the size-media-ted osteo-coagulo-immunomodulation. Based on the hierarchical levels of bone and its osteo-coagulo-immunomodulation effect, we provide a new understanding of the biological principle of the size effect of biomaterials and a theoretical basis for the basic research and clinical application of different size BHA materials.

Key words: biological hydroxyapatite, biomimetic hierarchical evolution, osteo-coagulo-immunomodulation, material size effect

中图分类号:

R318.08

许洁芸, 赵原, 刘浩州, 尹靖元, 陈泽涛. 生物源性钙磷灰石尺寸引发的骨仿生层级演变及其骨凝血免疫效应[J]. 华西口腔医学杂志, 2024, 42(6): 706-715.

Xu Jieyun, Zhao Yuan, Liu Haozhou, Yin Jingyuan, Chen Zetao. Hierarchical evolution of bone biomimicry and osteo-coagulo-immunomodulation induced by the size of biological hydroxyapatite[J]. West China Journal of Stomatology, 2024, 42(6): 706-715.

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参考文献 55

1	Zubieta-Otero LF, Londoño-Restrepo SM, Lopez-Cha-vez G, et al. Comparative study of physicochemical pro-perties of bio-hydroxyapatite with commercial samples[J]. Mater Chem Phys, 2021, 259: 124201.
2	Lebre F, Sridharan R, Sawkins MJ, et al. The shape and size of hydroxyapatite particles dictate inflammatory responses following implantation[J]. Sci Rep, 2017, 7(1): 2922.
3	Gao Y, Gao S, Yao Y, et al. Hard tissue stability outside the buccal bone arch contour after guided bone regeneration in the anterior maxilla: a retrospective cohort radiographic study[J]. Clin Oral Implants Res, 2023, 34(12): 1373-1384.
4	Reznikov N, Shahar R, Weiner S. Bone hierarchical stru-cture in three dimensions[J]. Acta Biomater, 2014, 10(9): 3815-3826.
5	Wu S, Shan Z, Xie L, et al. Mesopore controls the respon-ses of blood clot-immune complex via modulating fibrin network[J]. Adv Sci (Weinh), 2022, 9(3): e2103608.
6	Lange T, Schilling AF, Peters F, et al. Proinflammatory and osteoclastogenic effects of beta-tricalciumphosphate and hydroxyapatite particles on human mononuclear cells in vitro [J]. Biomaterials, 2009, 30(29): 5312-5318.
7	Shanley LC, Mahon OR, O'Rourke SA, et al. Macrophage metabolic profile is altered by hydroxyapatite particle size[J]. Acta Biomater, 2023, 160: 311-321.
8	Su M, Li C, Deng S, et al. Balance between the CMC/ACP nano complex and blood assimilation orchestrates immunomodulation of the biomineralized collagen matrix[J]. ACS Appl Mater Interfaces, 2023, 15(50): 58166-58180.
9	Zou Y, Shan Z, Han Z, et al. Regulating blood clot fibrin films to manipulate biomaterial-mediated foreign body responses[J]. Research (Wash D C), 2023, 6: 0225.
10	Samavedi S, Whittington AR, Goldstein AS. Calcium phosphate ceramics in bone tissue engineering: a review of properties and their influence on cell behavior[J]. Acta Biomater, 2013, 9(9): 8037-8045.
11	Henn V, Slupsky JR, Gräfe M, et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells[J]. Nature, 1998, 391(6667): 591-594.
12	Wang W, Yeung KWK. Bone grafts and biomaterials substitutes for bone defect repair: a review[J]. Bioact Mater, 2017, 2(4): 224-247.
13	Sanz-Sánchez I, Sanz-Martín I, Ortiz-Vigón A, et al. Complications in bone-grafting procedures: classification and management[J]. Periodontol 2000, 2022, 88(1): 86-102.
14	Sohn HS, Oh JK. Review of bone graft and bone substitutes with an emphasis on fracture surgeries[J]. Biomater Res, 2019, 23: 9.
15	Tay JRH, Lu XJ, Lai WMC, et al. Clinical and histological sequelae of surgical complications in horizontal gui-ded bone regeneration: a systematic review and proposal for management[J]. Int J Implant Dent, 2020, 6(1): 76.
16	Wongin S, Narkbunnam R, Waikakul S, et al. Construction and evaluation of osteochondral-like tissue using chondrocyte sheet and cancellous bone[J]. Tissue Eng Part A, 2021, 27(3/4): 282-295.
17	Nagasaki T, Nagata F, Sakurai M, et al. Effects of pore distribution of hydroxyapatite particles on their protein adsorption behavior[J]. J Asian Ceram Soc, 2017, 5(2): 88-93.
18	Yang Q, Zhang Y, Liu M, et al. Study of fibrinogen adsorption on hydroxyapatite and TiO₂ surfaces by electrochemical piezoelectric quartz crystal impedance and FTIR-ATR spectroscopy[J]. Anal Chim Acta, 2007, 597(1): 58-66.
19	Arimura S, Kawahara K, Biswas KK, et al. Hydroxyapatite formed on/in agarose gel induces activation of blood coagulation and platelets aggregation[J]. J Biomed Mater Res B Appl Biomater, 2007, 81(2): 456-461.
20	Liu Q, Chen Z, Gu H, et al. Preparation and characterization of fluorinated porcine hydroxyapatite[J]. Dent Mater J, 2012, 31(5): 742-750.
21	Qiao W, Liu R, Li Z, et al. Contribution of the in situ release of endogenous cations from xenograft bone driven by fluoride incorporation toward enhanced bone regeneration[J]. Biomater Sci, 2018, 6(11): 2951-2964.
22	Liu R, Qiao W, Huang B, et al. Fluorination enhances the osteogenic capacity of porcine hydroxyapatite[J]. Tis-sue Eng Part A, 2018, 24(15/16): 1207-1217.
23	Ferraz N, Carlsson J, Hong J, et al. Influence of nanoporesize on platelet adhesion and activation[J]. J Mater Sci Mater Med, 2008, 19(9): 3115-3121.
24	Zhou H, Wang C, Niu H, et al. A novel droplet-fabrica-ted mesoporous silica-based nanohybrid granules for he-morrhage control[J]. J Biomed Nanotechnol, 2018, 14(4): 649-661.
25	Han YC, Wang XY, Dai HL, et al. Nanosize and surface charge effects of hydroxyapatite nanoparticles on red blood cell suspensions[J]. ACS Appl Mater Interfaces, 2012, 4(9): 4616-4622.
26	Zhao Y, Sun X, Zhang G, et al. Interaction of mesoporous silica nanoparticles with human red blood cell me-mbranes: size and surface effects[J]. ACS Nano, 2011, 5(2): 1366-1375.
27	Rouahi M, Gallet O, Champion E, et al. Influence of hydroxyapatite microstructure on human bone cell response[J]. J Biomed Mater Res A, 2006, 78(2): 222-235.
28	Ferraz N, Ott MK, Hong J. Time sequence of blood activation by nanoporous alumina: studies on platelets and complement system[J]. Microsc Res Tech, 2010, 73(12): 1101-1109.
29	Macrae FL, Duval C, Papareddy P, et al. A fibrin biofilm covers blood clots and protects from microbial invasion[J]. J Clin Invest, 2018, 128(8): 3356-3368.
30	Weisel JW, Litvinov RI. Keeping it clean: clot biofilm to wall out bacterial invasion[J]. J Thromb Haemost, 2018, 16(12): 2359-2361.
31	Weisel JW, Litvinov RI. Fibrin formation, structure and properties[M]//Parry DAD, Squire JM. Fibrous proteins: structures and mechanisms. Berlin: Springer, 2017: 405-456.
32	Garg K, Pullen NA, Oskeritzian CA, et al. Macrophage functional polarization (M1/M2) in response to varying fiber and pore dimensions of electrospun scaffolds[J]. Biomaterials, 2013, 34(18): 4439-4451.
33	Ooi CH, Ling YP, Abdullah WZ, et al. Physicochemical evaluation and in vitro hemocompatibility study on nanoporous hydroxyapatite[J]. J Mater Sci Mater Med, 2019, 30(4): 44.
34	Wang J, Wang L, Fan Y. Adverse biological effect of TiO₂ and hydroxyapatite nanoparticles used in bone repair and replacement[J]. Int J Mol Sci, 2016, 17(6): E798.
35	Kandori K, Fudo A, Ishikawa T. Study on the particle texture dependence of protein adsorption by using synthetic micrometer-sized calcium hydroxyapatite particles[J]. Colloids Surf B Biointerfaces, 2002, 24(2): 145-153.
36	Kawachi G, Sasaki S, Nakahara K, et al. Porous apatite carrier prepared by hydrothermal method[J]. Key Eng Mater, 2006, 309-311(2): 935-938.
37	Aslam Khan MU, Haider A, Abd Razak SI, et al. Arabinoxylan/graphene-oxide/nHAp-NPs/PVA bionano composite scaffolds for fractured bone healing[J]. J Tissue Eng Regen Med, 2021, 15(4): 322-335.
38	Santos C, Turiel S, Sousa Gomes P, et al. Vascular biosafety of commercial hydroxyapatite particles: discrepancy between blood compatibility assays and endothelial cell behavior[J]. J Nanobiotechnol, 2018, 16(1): 27.
39	Cazalbou S, Combes C, Eichert D, et al. Adaptative physico-chemistry of bio-related calcium phosphates[J]. J Mater Chem, 2004, 14(14): 2148-53.
40	Rey C, Combes C. What bridges mineral platelets of bone[J]. Bonekey Rep, 2014, 3: 586.
41	Habraken W, Habibovic P, Epple M, et al. Calcium phosphates in biomedical applications: materials for the future[J]. Mater Today, 2016, 19(2): 69-87.
42	Beniash E, Metzler RA, Lam RS, et al. Transient amorphous calcium phosphate in forming enamel[J]. J Struct Biol, 2009, 166(2): 133-143.
43	Lyu Y, Asoh TA, Uyama H. Facile synthesis of a three-dimensional hydroxyapatite monolith for protein adsorption[J]. J Mater Chem B, 2021, 9(47): 9711-9719.
44	Perez RA, Mestres G. Role of pore size and morphology in musculo-skeletal tissue regeneration[J]. Mater Sci Eng C Mater Biol Appl, 2016, 61: 922-939.
45	Mehmani A, Prodanovic M. The effect of microporosity on transport properties in porous media[J]. Adv Water Resour, 2014, 63: 104-119.
46	Pérez RA, Won JE, Knowles JC, et al. Naturally and synthetic smart composite biomaterials for tissue regeneration[J]. Adv Drug Deliv Rev, 2013, 65(4): 471-496.
47	Oh DS, Kim YJ, Hong MH, et al. Effect of capillary action on bone regeneration in micro-channeled ceramic scaffolds[J]. Ceram Int, 2014, 40(7): 9583-9589.
48	Li X, van Blitterswijk CA, Feng Q, et al. The effect of calcium phosphate microstructure on bone-related cells in vitro [J]. Biomaterials, 2008, 29(23): 3306-3316.
49	Wang Y, Zhang X, Shao J, et al. Adiponectin regulates BMSC osteogenic differentiation and osteogenesis th-rough the Wnt/β-catenin pathway[J]. Sci Rep, 2017, 7(1): 3652.
50	Cicuéndez M, Malmsten M, Doadrio JC, et al. Tailoring hierarchical meso-macroporous 3D scaffolds: from nano to macro[J]. J Mater Chem B, 2014, 2(1): 49-58.
51	Ain QU, Zeeshan M, Mazhar D, et al. QbD-based fabrication of biomimetic hydroxyapatite embedded gelatin nanoparticles for localized drug delivery against deteriorated arthritic joint architecture[J]. Macromol Biosci, 2024, 24(2): e2300336.
52	Ravichandran R, Gandhi S, Sundaramurthi D, et al. Hierarchical mesoporous silica nanofibers as multifunctional scaffolds for bone tissue regeneration[J]. J Biomater Sci Polym Ed, 2013, 24(17): 1988-2005.
53	Hulbert SF, Young FA, Mathews RS, et al. Potential of ceramic materials as permanently implantable skeletal prostheses[J]. J Biomed Mater Res, 1970, 4(3): 433-456.
54	Roseti L, Parisi V, Petretta M, et al. Scaffolds for bone tissue engineering: state of the art and new perspectives[J]. Mater Sci Eng C Mater Biol Appl, 2017, 78: 1246-1262.
55	O'brien FJ. Biomaterials & scaffolds for tissue enginee-ring[J]. Mater Today, 2011, 14(3): 88-95.

品牌名称	产地	材料来源	颗粒尺寸
Bio-Oss^?	美国	牛骨	0.25~1 mm；1~2 mm
THE Graft?	中国	猪骨	0.25~1 mm；1~2 mm
Gen-Os^?	英国	猪骨或马骨	0.25~1 mm
Cerabone^?	瑞士	牛骨	0.5~1 mm；1~2 mm
Endobon^?	法国	牛骨	0.5~1 mm；1~2 mm
OsteoGraf^?	美国	牛骨	0.25~0.42 mm；0.42~1 mm
SYMBIOS^?	美国	海藻	0.2~1 mm；1~2 mm
Bio Osteo^?	中国	牛骨	0.25~1 mm；0.4~1 mm；1~2 mm
Adbone^?	葡萄牙	异种骨	0.1~0.5 mm；1~2 mm
BioBase a-pore^?	德国	牛骨	0.25~0.5 mm；0.5~1.4 mm；1.4~3.2 mm
Genoss^?	韩国	猪骨	0.2~0.5 mm；0.5~1 mm；1~2 mm
ChronOS^?	美国	异种骨	0.5~0.7 mm；0.7~1.4 mm；1.4~2.8 mm
BioResorb^?	德国	异种骨	0.2~0.5 mm；0.5~1 mm；1~2 mm
Frios Algipore^?	美国	海藻	0.3~0.5 mm；0.5~1 mm

分级	名称	结构特征	基本结构尺寸
一级	骨骼基本成分	单纯BHA晶体或胶原纤维	BHA晶体长30~50 nm，宽20~25 nm，厚1.5~4 nm
二级	骨骼基础结构	BHA晶体和矿化胶原纤维组成	胶原纤维尺寸0.1 μm左右
三级	纤维阵列	Ⅰ型胶原蛋白组成的三维螺旋结构的纤维阵列	阵列结构尺寸处于小于一个微米到数个微米之间
四级	阵列模式	纤维阵列组成阵列模式，分为平行/扇形模式	板层骨和平行纤维骨尺寸约为1 μm
五级	超结构	分为有序骨中的单向胶原纤维束和无序骨中的骨陷窝-骨小管网络	纤维束直径1~3 μm，相邻纤维束相距67 nm
六级	骨组织	构成骨骼的组织包括编织骨、平行纤维骨和板层骨	骨组织直径10 μm左右，板层间厚度3~7 μm
七级	组织结构基序	4种类型，环形板层基序、板层束、骨单位和纤维层状骨	哈弗系统由直径100~200 μm的圆柱状结构和30~40 μm的中央管形成
八级	组织	密质骨或松质骨	密质骨尺寸约1 mm，松质骨直径0.1~3.5 mm
九级	组织	密质骨和松质骨	密质骨、松质骨尺寸都为毫米级别

尺寸	骨仿生层级
<0.2 mm	仅保留生物骨的第一至第六级结构，其比表面积和纳米至微米级微孔比例最高
0.2~1 mm	保留生物骨的第一至第七级结构和部分第八级结构（尺寸小于等于1 mm松质骨结构），其比表面积和微孔占比居中
>1 mm	保留生物骨的第一至第七级结构和大部分第八级结构（尺寸大于1 mm的松质骨结构），其比表面积和微孔占比最低

尺寸	层级	结构	骨凝血免疫调控潜能
<0.2 mm	一级	钙磷灰石晶体	其晶体、堆积面和离子活性影响凝血系统的活性
	二级	微孔/网孔	提供吸附位点，增加凝血启动信号和官能团暴露，促进凝血因子与周围物质进行离子交换
	三级	单层骨小梁结构	增加血小板分散活性、凝血因子吸附面积，材料支架无法提供稳定的空间支持
0.2~1 mm	四级	单层大孔结构	提供血凝块基本支架，确保血凝块与材料机械嵌合，促进血管生长及细胞渗透，提升骨再生能力
>1 mm	五级	多层多孔结构	促进血浆蛋白循环，为成骨细胞黏附、增殖提供环境

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生物源性钙磷灰石尺寸引发的骨仿生层级演变及其骨凝血免疫效应

Hierarchical evolution of bone biomimicry and osteo-coagulo-immunomodulation induced by the size of biological hydroxyapatite

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