Bioactive Materials for Bone Regeneration

241 Pages·2019·16.007 MB·English

by  Jiang Chang, Xingdong Zhang, Kerong Dai

Bioactive Materials for
Bone Regeneration
Jiang Chang
Biomaterials and Tissue Engineering Research Center
Shanghai Institute of Ceramics
Chinese Academy of Sciences
Shanghai, Shanghai, China
Xingdong Zhang
National Engineering Research Center for Biomaterials
Sichuan University
Chengdu, Sichuan, China
Kerong Dai
Shanghai Ninth People’s Hospital
Shanghai Jiaotong University School of Medicine
Shanghai, Shanghai, China
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Preface
Severalthousandyearsagopeoplebeganusingmaterialstofixdamagedtissue
such as bones and teeth, and nowadays different materials including metals,
ceramics,andpolymersarewidelyusedfororthopedicanddentalapplications.
In most of these clinical applications, we mainly utilize physical properties
of materials such as mechanical support, physical coverage, and mechanical
fixation to support bone regeneration. However, with increased economic
development and an aging population, regenerative medicine is facing new
challenges and questions that need to be answered including how to enhance
chronic wound healing, heal aging people or patients with osteoporosis, and
reduce bone healing time (reduction in treatment time and costs). One of the
fundamental questions is whether, instead of physical support for bone regen-
eration, biomaterials have biological activities that can actively stimulate the
bone-healingprocess.
In recent years, many studies have shown that specific structural and
chemicalmaterialsignalssuchasthesurfacemicro-/nanostructureofbonegraft
materials and ions released from bioceramics and bioactive glasses indeed
have activity to stimulate bone regeneration through the regulation of cell
proliferation, stem cell differentiation, cellecell interaction, and macrophage
polarization.However,howthesematerialsignalsactivatethebiologicalsystem
and their related mechanisms are still unclear. Elucidating the mechanisms of
biomaterialsinstimulatingcellularactivityandboneregenerationwillprovide
importantinformationfordesigningoptimalmaterialsforboneregeneration.
WiththesupportoftheNaturalScienceFoundationofChina,weconducteda
five-year project to investigate bioactive bone-regeneration materials with an
emphasis on the aforementioned scientific questions, and these studies have
resulted inthe establishment ofseveralresearch teamswith extended research
collaboration nationally and internationally. These studies have also further
extended our knowledge about the interaction between biomaterials and bio-
logical systems and our understanding of the bioactivity of bone-regeneration
biomaterials. We believe that the concept of bioactive materials with biolog-
ical activity derived from pure materials may significantly contribute to the
developmentofnew-generationbiomaterialsforregenerativemedicine.There-
fore,withthehelpofprojectteammembersandtheircollaborators,wedecided
ix
x Preface
to edit this book, which summarizes related studies in the field of bone bio-
materials and gives an overview of updated research progress on bioactive
materialsforboneregeneration.Wehopethisbookmaybeinterestingforsci-
entists,engineers,andgraduatestudentsinbiomedicalengineeringandprovide
useful information for the development of new-generation biomaterials for
regenerativemedicine.
JiangChang
XingdongZhang
KerongDai
Chapter 1
Material characteristics,
surface/interface, and
biological effects on the
osteogenesis of bioactive
materials
Chapter outline
1.1 Fabricationmethodsof 1.1.3.2.1 Bonelike
bioactivematerialsforbone apatitefor-
regeneration 3 mation 14
1.1.1 Materialcharacteristicsof 1.1.3.2.2 Nanoscale
bioactivematerialsforbone topography 14
regeneration 4 1.1.3.2.3 Whisker
1.1.1.1 Chemicalcomposition 4 reinforce-
1.1.1.2 Porousstructure 4 ment 15
1.1.1.3 Surfacemicro-and 1.1.3.2.4 Traceion
nanostructure 5 doping 16
1.1.2 Designofporousbioactive References 16
materials 6 1.2 Surfacemicro-/nanostructure
1.1.2.1 Synthesisofinitial regulationofbioactive
nanopowderand materialsforosteogenesis 26
precursor 6 1.2.1 Surfacemorphologyof
1.1.2.2 Moldingofporous bioactivematerialsfor
structure 7 osteogenesis 26
1.1.2.3 Sinteringtechnologies 9 1.2.1.1 Orderlymicropatterned
1.1.2.4 Surfacemodification surfacemorphologyof
methods 11 calciumphosphatee
1.1.3 Mainchallengesandprospects 12 basedbioceramics 26
1.1.3.1 Mainchallengesof 1.2.1.2 Randomlystructured
bioactivematerials 12 surfacemorphologyof
1.1.3.2 Enhancingbioactivity calciumphosphatee
andmechanical basedbioceramics 29
propertymethods 14
BioactiveMaterialsforBoneRegeneration.https://doi.org/10.1016/B978-0-12-813503-7.00001-7
Copyright©2020HigherEducationPress.PublishedbyElsevierLtd.Allrightsreserved. 1
2 BioactiveMaterialsforBoneRegeneration
1.2.1.2.1 Hydrother- 1.3.2.2 Interactionsbetween
maltreat- proteinsandbioactive
mentof materials 61
randomly 1.3.3 Theeffectofproteinadsorption
structured ontheosteogenesisofbioactive
surface materials 62
morphology 29 1.3.3.1 Extracellularprotein
1.2.1.2.2 Simulated adsorption 63
bodyfluid 1.3.3.2 Adsorptionofspecific
immersion proteins(bone
and morphogenetic
inducingof proteinsand
randomcal- transcriptiongrowth
ciumphos- factorbeta) 65
phatesur- 1.3.3.3 Othergrowthfactor
face adsorption 67
morphology 31 1.3.3.4 Cytokineadsorption 67
1.2.1.2.3 Otherfabri- 1.3.4 Summary 68
cation References 69
methodsof 1.4 Osteogenesisinducedby
randomly bioactiveporousmaterialsand
structured therelatedmolecular
surface mechanism 79
morphology 33 1.4.1 Angiogenesisofbioactive
1.2.2 Porosityofbioactiveporous materialsandtheinvolved
materialsforosteogenesis 35 molecularmechanism 79
1.2.3 Grainsizeofbioactive 1.4.2 Osteogenesisofbioactive
materialsforosteogenesis 36 materialsandmaterial-
1.2.3.1 Microscaleand mediatedmesenchymalstem
submicroscalegrain cellfunction 82
sizes 36 1.4.2.1 Osteogenicionic
1.2.3.2 Nanoscalegrainsize 40 environmentcreatedin
1.2.4 Summary 44 theporousstructure 82
References 44 1.4.2.1.1 Ca2þ
1.3 Proteinadsorptiononbioactive gradient 82
materialsanditseffecton 1.4.2.1.2 PO3(cid:2)inter-
4
osteogenesis 53 nalization 84
1.3.1 Currentmethodsforstudying 1.4.2.2 Cellsoforiginand
proteinadsorption 53 cellulareventsin
1.3.1.1 Experimentalmethods 53 material-induced
1.3.1.2 Computingmethods 54 osteogenesis 84
1.3.2 Materialfactorsinfluencing 1.4.2.2.1 Cellsof
proteinadsorption 56 origin 84
1.3.2.1 Materialfactors 56 1.4.2.2.2 Eventsat
1.3.2.1.1 Topography 56 cellularlevel 86
1.3.2.1.2 Chemical 1.4.2.3 Osteogenicmechanism
properties 58 ofbioactiveporous
1.3.2.1.3 Hydropho- titanium 88
bicity 60 1.4.3 Roleofimmunoresponseinthe
osteogenesisofbioactive
materials 90
Materialcharacteristics,surface/interface Chapter | 1 3
1.4.3.1 Autocrineeffectof 1.4.3.2 Paracrineeffectfrom
mesenchymalstem immunecells 92
cells 90 1.4.4 Summary 95
References 96
Bioactive materials play an increasingly important role in regenerative
medicineandtissueengineeringforbone.Manyreportshave shownthatthe
biological properties of bioactive materials depend greatly on material
characteristicsandsurface/interfaceproperties.Therefore,thischapterfirstly
focuses on different fabrication methods for the preparation of bone regen-
erative biomaterials with an emphasis on accurate control of material char-
acteristics such as chemical composition, macro-/microstructure, and
mechanical properties. Methods for surface modification of bone regenera-
tive biomaterials and evaluation of physicochemical properties of prepared
materials are also introduced. Protein adsorption is the initial event after
implantation of a biomaterial and directly influences subsequent cell
behavior and implant fate. This chapter introduces the interactions between
bone regenerative biomaterials and various bone-related proteins and dis-
cusses the key contributions of adsorbed functional proteins in biomaterials
tomaterial-inducedboneregeneration.Thecellisthefundamentalunitofthe
human body, and the behavior of cells under the influence of biomaterials
determinestheprogressofboneregenerationandrepair.Finally,thischapter
elucidates the interactions of bone regenerative biomaterials with cells and
tissuesandthespecificeffectsofmaterialcharacteristicsonosteogenesisand
the involved molecular mechanism.
Chapter 1.1
Fabrication methods of bioactive
materials for bone regeneration
Inspired by the concept of regenerative medicine, the design of biomaterials
with tissue-inducing abilities is a new direction for bioactive materials.
Bioactive materials should be bioactive not only to bond with the tissue
interface, but also to induce tissue regeneration, thus permanently healing
damaged or missing tissues and organs. This discovery of material osteoin-
ductivity indicates that materials might be endowed with the biofunction of
inducing tissue regeneration, thus making them hopeful solutions for estab-
lishing tissue function through optimized design ofthe material itself without
adding any living cells or growth factors. That is to say, fabrication methods
are quite important for bioactive materials, as they are critical to biological
performance in bone regeneration.
4 BioactiveMaterialsforBoneRegeneration
1.1.1 Material characteristics of bioactive materials for
bone regeneration
1.1.1.1 Chemical composition
Among the current bone substitute materials, calcium phosphate (Ca-P) ce-
ramicsundoubtedlyhavethemostpotentialowingtotheirsimilarcomposition
to that of the bone mineral as well as their confirmed biocompatibility,
osteoconductivity, and osteoinductivity. The most studied Ca-P ceramics are
hydroxyapatite(HA),b-TCP,andBCP(HA/b-TCP)[1e4].Amongthem,HA
is the most stable and occasionally achieves osteoinductivity due to its low
dissolution rate. The solubility of b-TCP is much higher than that of HA, but
the fast dissolution rate makes it difficult to retain the basic mechanical sup-
portforthedesiredduration[5].Therefore,biphasiccalciumphosphate(BCP)
with different b-TCP/HA ratios can achieve optimum solubility and good
osteoinductivity [1,2,4e7]. Our previous work compared the osteoinductivity
of BCP ceramics with different b-TCP/HA ratios, the results demonstrating
thatBCPwithab-TCP/HAratioof3/7couldpromoteBMP-2expressionand
owned a higher osteoinductivity than those of BCP of 7/3, pure b-TCP, and
HA ceramics [2]. Our present work introduced a novel alginate gelatinizing
technologytostabilizeCa-deficienthydroxyapatite(CDHA)inBCPceramics;
theobtainedBCPceramicswithahighCDHAphasecontentshowedexcellent
bioactivity and osteoinductivity because the the composition of CDHA was
closer to that of bony mineral [8]. Furthermore, the osteoinductivity of non-
ceramic Ca-P materials (i.e., Ca-P cements, Ca-P composites) was usually
weaker than that of Ca-P ceramics, partly due to the lack of a 3D porous
structure and high solubility.
Silicon (Si) is one of the indispensable trace elements in the human body,
foundinextracellularmatrixcompoundsandbone[9,10].ItwasreportedthatSi
is mainly distributed in the active calcification sites of bone and directly
involved in the bony mineralization process [9,11]. Up to now, many kinds of
Si-basedbioactivematerialshavebeendevelopedandwidelyapplied.Research
emphases include ceramic preparation methods, mechanical strength, apatite
mineralization,dissolution,bioactiveproperties,andcorrespondingmechanisms
[12e14]. Due to their variable chemical compositions, the physical, chemical,
and biological properties could be well optimized to satisfy the varied re-
quirementsoftissueregeneration[9].Oneofthemostpopularsilicateceramics
isbioglass,whichhasbeenapprovedbytheFDAandemployedfororthopedic
applications in clinic under the name NovaBone@ [15e17].
1.1.1.2 Porous structure
3D porous structures also play a critical role in determining the osteoinduc-
tivity of materials. Osteoinductivity is generally observed in porous Ca-P
Materialcharacteristics,surface/interface Chapter | 1 5
ceramics, while dense Ca-P ceramics cannot induce bone formation [18,19].
The porous structure mainly facilitates the exchange of oxygen and nutrition
andallowstissue,blood,andcellstomigratethescaffoldinterior[1,4,18e21].
It iswell known thatporestructure parameters(i.e.,porosity, shape,size,and
connectivity) have a great influence on the biological performance of scaf-
folds. Generally, high porosity is beneficial to osteogenesis, but the scaffold
strength with overly high porosity is too low to provide stable support during
the implantation process [1]. It is generally believed that a porosity ranging
from 40% to 80% is suitable for bone repair. Moreover, pore connectivity is
related to osteogenesis, and the connected pores allow nutrients, cells, and
tissue to grow into the inner part of the scaffolds [1,4,22,23]. Yuan HP et al.
observedthatnewbonewasmainlygeneratedintheinterioroftheperipheral
channels (close to the openings) of DCPA cement bulk in goat intramuscular
implantation [24]. Much previous research has also certified that the suitable
pore diameter for bone-repairing scaffolds is about 200e600mm, and a con-
nected pore size within a range of 50e200mm is relatively optimal [1,4].
Moreover,micropores(<10mm)playanimportantroleindeterminingthe
osteoinductivity of implanted scaffolds, which not only facilitate the pene-
tration of body fluids but also promote cell attachment and osteogenic dif-
ferentiation due to increased surface roughness [1,3,4,6,18,19]. Some work
also has proved that internal pores could confine the flow of body fluid and
create a local high concentration of Ca2þ and PO3(cid:2) in the pores as well as
4
decreasetheshearstressesexertedontheattachedcellsandproteins[18].Our
previous work found that HA and BCP particles with high porosity and
abundantmicropores(>20nm)couldadsorbmorefibrinogenandinsulinthan
particles with low porosity [25]. We further certified that the distribution of
micropores on the walls of macropores favored the adsorption of low-
molecular-weight proteins [26]. These studies strongly indicate that high
levels of micropores in Ca-P ceramics favor protein adsorption that in turn
induces osteogenesis.
1.1.1.3 Surface micro- and nanostructure
Surfacemicro-andnanostructurealsoareanimportantfactorforinducingthe
bioactivity of biomaterials. Many studies have investigated the effects of
surfacetopographyoncellularbehaviors(i.e.,celladhesion,proliferation,and
differentiation [27e33]. Dalby MJ et al. [34,35] fabricated several kinds of
surface topographies with nanostructure and observed that the responses of
mesenchymalstemorstromalcells(MSCs)weregreatlyinfluencedbysurface
topography. A kind of nanodisplaced topography could significantly promote
osteospecific differentiation; further study found that the disordered nanopit
pattern could induce osteogenic differentiation, while symmetric and random
nanopit arrays could not. For Ca-P ceramics, surface topography can be
tailored by adjusting their grain sizes. Osteoinductivity of BCP ceramics