PDF Bioactive Materials For Bone Regeneration 1St Edition Jiang Chang Ebook Full Chapter

Bioactive Materials for Bone
Regeneration 1st Edition Jiang Chang

Visit to download the full and correct content document:
https://textbookfull.com/product/bioactive-materials-for-bone-regeneration-1st-edition-j
iang-chang/
More products digital (pdf, epub, mobi) instant
download maybe you interests ...
Development of China s Cultural Industry Chang Jiang
https://textbookfull.com/product/development-of-china-s-cultural-
industry-chang-jiang/
Mesoporous materials for advanced energy storage and

conversion technologies 1st Edition Jiang
https://textbookfull.com/product/mesoporous-materials-for-
advanced-energy-storage-and-conversion-technologies-1st-edition-
jiang/
Mesoporous Materials for Advanced Energy Storage and

Conversion Technologies 1st Edition San Ping Jiang
san-ping-jiang/
Mesoporous Materials for Advanced Energy Storage and

Conversion Technologies 1st Edition San Ping Jiang
san-ping-jiang-2/
Bioactive Glasses, Second Edition: Materials,
Properties and Applications Heimo Ylänen
https://textbookfull.com/product/bioactive-glasses-second-
edition-materials-properties-and-applications-heimo-ylanen/
Bone Response to Dental Implant Materials 1st Edition

Adriano Piattelli
https://textbookfull.com/product/bone-response-to-dental-implant-
materials-1st-edition-adriano-piattelli/
Tissue Engineering Strategies for Organ Regeneration

1st Edition Naznin Sultana (Editor)
https://textbookfull.com/product/tissue-engineering-strategies-
for-organ-regeneration-1st-edition-naznin-sultana-editor/
Bioactive Natural Products for Pharmaceutical

Applications Dilipkumar Pal
https://textbookfull.com/product/bioactive-natural-products-for-
pharmaceutical-applications-dilipkumar-pal/
Housing Regeneration: A Plan for Implementation Charles

Ward
https://textbookfull.com/product/housing-regeneration-a-plan-for-
implementation-charles-ward/
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
Academic Press is an imprint of Elsevier
125 London Wall, London EC2Y 5AS, United Kingdom
525 B Street, Suite 1650, San Diego, CA 92101, United States
50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States
The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom
Copyright © 2020 Higher Education Press. Published by Elsevier Ltd. All rights reserved.
No part of this publication may be reproduced or transmitted in any form or by any means,
electronic or mechanical, including photocopying, recording, or any information storage
and retrieval system, without permission in writing from the publisher. Details on how to
seek permission, further information about the Publisher’s permissions policies and our
arrangements with organizations such as the Copyright Clearance Center and the Copyright
Licensing Agency, can be found at our website: www.elsevier.com/permissions.
This book and the individual contributions contained in it are protected under copyright by
the Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this ﬁeld are constantly changing. As new research and
experience broaden our understanding, changes in research methods, professional
practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in
evaluating and using any information, methods, compounds, or experiments described
herein. In using such information or methods they should be mindful of their own safety
and the safety of others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or
editors, assume any liability for any injury and/or damage to persons or property as a matter
of products liability, negligence or otherwise, or from any use or operation of any methods,
products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress
British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library
ISBN: 978-0-12-813503-7
For information on all Academic Press publications visit our

website at https://www.elsevier.com/books-and-journals
Publisher: Matthew Deans

Acquisitions Editor: Glyn Jones
Editorial Project Manager: Naomi Robertson
Production Project Manager: Sojan P. Pazhayattil
Cover Designer: Christian J. Bilbow
Typeset by TNQ Technologies

Preface
Several thousand years ago people began using materials to fix damaged tissue
such as bones and teeth, and nowadays different materials including metals,
ceramics, and polymers are widely used for orthopedic and dental applications.
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-healing process.
In recent years, many studies have shown that specific structural and
chemical material signals such as the surface micro-/nanostructure of bone graft
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, how these material signals activate the biological system
and their related mechanisms are still unclear. Elucidating the mechanisms of
biomaterials in stimulating cellular activity and bone regeneration will provide
important information for designing optimal materials for bone regeneration.
With the support of the Natural Science Foundation of China, we conducted a
five-year project to investigate bioactive bone-regeneration materials with an
emphasis on the aforementioned scientific questions, and these studies have
resulted in the establishment of several research teams with 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
development of new-generation biomaterials for regenerative medicine. There-
fore, with the help of project team members and their collaborators, we decided
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
materials for bone regeneration. We hope this book may be interesting for sci-
entists, engineers, and graduate students in biomedical engineering and provide
useful information for the development of new-generation biomaterials for
regenerative medicine.
Jiang Chang
Xingdong Zhang
Kerong Dai
Chapter 1
Material characteristics,
surface/interface, and
biological effects on the
osteogenesis of bioactive
materials
Chapter outline
1.1 Fabrication methods of 1.1.3.2.1 Bonelike
bioactive materials for bone apatite for-
regeneration 3 mation 14
1.1.1 Material characteristics of 1.1.3.2.2 Nanoscale
bioactive materials for bone topography 14
regeneration 4 1.1.3.2.3 Whisker
1.1.1.1 Chemical composition 4 reinforce-
1.1.1.2 Porous structure 4 ment 15
1.1.1.3 Surface micro- and 1.1.3.2.4 Trace ion
nanostructure 5 doping 16
1.1.2 Design of porous bioactive References 16
materials 6 1.2 Surface micro-/nanostructure
1.1.2.1 Synthesis of initial regulation of bioactive
nanopowder and materials for osteogenesis 26
precursor 6 1.2.1 Surface morphology of
1.1.2.2 Molding of porous bioactive materials for
structure 7 osteogenesis 26
1.1.2.3 Sintering technologies 9 1.2.1.1 Orderly micropatterned
1.1.2.4 Surface modification surface morphology of
methods 11 calcium phosphatee
1.1.3 Main challenges and prospects 12 based bioceramics 26
1.1.3.1 Main challenges of 1.2.1.2 Randomly structured
bioactive materials 12 surface morphology of
1.1.3.2 Enhancing bioactivity calcium phosphatee
and mechanical based bioceramics 29
property methods 14
Bioactive Materials for Bone Regeneration. https://doi.org/10.1016/B978-0-12-813503-7.00001-7

Copyright © 2020 Higher Education Press. Published by Elsevier Ltd. All rights reserved. 1
2 Bioactive Materials for Bone Regeneration
1.2.1.2.1 Hydrother- 1.3.2.2 Interactions between

mal treat- proteins and bioactive
ment of materials 61
randomly 1.3.3 The effect of protein adsorption
structured on the osteogenesis of bioactive
surface materials 62
morphology 29 1.3.3.1 Extracellular protein
1.2.1.2.2 Simulated adsorption 63
body fluid 1.3.3.2 Adsorption of specific
immersion proteins (bone
and morphogenetic
inducing of proteins and
random cal- transcription growth
cium phos- factor beta) 65
phate sur- 1.3.3.3 Other growth factor
face adsorption 67
morphology 31 1.3.3.4 Cytokine adsorption 67
1.2.1.2.3 Other fabri- 1.3.4 Summary 68
cation References 69
methods of 1.4 Osteogenesis induced by
randomly bioactive porous materials and
structured the related molecular
surface mechanism 79
morphology 33 1.4.1 Angiogenesis of bioactive
1.2.2 Porosity of bioactive porous materials and the involved
materials for osteogenesis 35 molecular mechanism 79
1.2.3 Grain size of bioactive 1.4.2 Osteogenesis of bioactive
materials for osteogenesis 36 materials and material-
1.2.3.1 Microscale and mediated mesenchymal stem
submicroscale grain cell function 82
sizes 36 1.4.2.1 Osteogenic ionic
1.2.3.2 Nanoscale grain size 40 environment created in
1.2.4 Summary 44 the porous structure 82
References 44 1.4.2.1.1 Ca2þ
1.3 Protein adsorption on bioactive gradient 82
materials and its effect on 1.4.2.1.2 PO34 inter-
osteogenesis 53 nalization 84
1.3.1 Current methods for studying 1.4.2.2 Cells of origin and
protein adsorption 53 cellular events in
1.3.1.1 Experimental methods 53 material-induced
1.3.1.2 Computing methods 54 osteogenesis 84
1.3.2 Material factors influencing 1.4.2.2.1 Cells of
protein adsorption 56 origin 84
1.3.2.1 Material factors 56 1.4.2.2.2 Events at
1.3.2.1.1 Topography 56 cellular level 86
1.3.2.1.2 Chemical 1.4.2.3 Osteogenic mechanism
properties 58 of bioactive porous
1.3.2.1.3 Hydropho- titanium 88
bicity 60 1.4.3 Role of immunoresponse in the
osteogenesis of bioactive
materials 90
Material characteristics, surface/interface Chapter | 1 3
1.4.3.1 Autocrine effect of 1.4.3.2 Paracrine effect from

mesenchymal stem immune cells 92
cells 90 1.4.4 Summary 95
References 96
Bioactive materials play an increasingly important role in regenerative

medicine and tissue engineering for bone. Many reports have shown that the
biological properties of bioactive materials depend greatly on material
characteristics and surface/interface properties. Therefore, this chapter firstly
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
to material-induced bone regeneration. The cell is the fundamental unit of the
human body, and the behavior of cells under the influence of biomaterials
determines the progress of bone regeneration and repair. Finally, this chapter
elucidates the interactions of bone regenerative biomaterials with cells and
tissues and the specific effects of material characteristics on osteogenesis and
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 of the 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.
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-
ramics undoubtedly have the most potential owing to their similar composition
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, and BCP (HA/b-TCP) [1e4]. Among them, 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-
port for the desired duration [5]. Therefore, biphasic calcium phosphate (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
that BCP with a b-TCP/HA ratio of 3/7 could promote BMP-2 expression and
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
technology to stabilize Ca-deficient hydroxyapatite (CDHA) in BCP ceramics;
the obtained BCP ceramics with a high CDHA phase content showed excellent
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,
found in extracellular matrix compounds and bone [9,10]. It was reported that Si
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-based bioactive materials have been developed and widely applied. Research
emphases include ceramic preparation methods, mechanical strength, apatite
mineralization, dissolution, bioactive properties, and corresponding mechanisms
[12e14]. Due to their variable chemical compositions, the physical, chemical,
and biological properties could be well optimized to satisfy the varied re-
quirements of tissue regeneration [9]. One of the most popular silicate ceramics
is bioglass, which has been approved by the FDA and employed for orthopedic
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
ceramics, while dense Ca-P ceramics cannot induce bone formation [18,19].
The porous structure mainly facilitates the exchange of oxygen and nutrition
and allows tissue, blood, and cells to migrate the scaffold interior [1,4,18e21].
It is well known that pore structure 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.
observed that new bone was mainly generated in the interior of the peripheral
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 200e600 mm, and a con-
nected pore size within a range of 50e200 mm is relatively optimal [1,4].
Moreover, micropores (<10 mm) play an important role in determining the
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 4 in the pores as well as
decrease the shear stresses exerted on the attached cells and proteins [18]. Our
previous work found that HA and BCP particles with high porosity and
abundant micropores (>20 nm) could adsorb more fibrinogen and insulin than
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

Surface micro- and nanostructure also are an important factor for inducing the
bioactivity of biomaterials. Many studies have investigated the effects of
surface topography on cellular behaviors (i.e., cell adhesion, proliferation, and
differentiation [27e33]. Dalby MJ et al. [34,35] fabricated several kinds of
surface topographies with nanostructure and observed that the responses of
mesenchymal stem or stromal cells (MSCs) were greatly influenced by surface
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
FIGURE 1.1 Material characteristics of bioactive porous materials for bone regeneration.
increased with decreasing crystal size, and the different surface microstructure
was regarded as an important factor affecting osteoinductivity [4,36]. The
surface pore structure is generally regarded as another important surface
topography that has an important influence on cell response, biofunctions, and
even osteogenic processes. Our previous work fabricated several kinds of pore
structures on HA-dense ceramic discs [37], and the results revealed that
macropore structures favored cell proliferation, while micropore structures
upregulated early osteoblastic differentiation. Another of our works fabricated
that HA ceramics with orderly micropatterned surfaces varied in groove width
[38] and found that cell response also changed with the micropatterns. Based
on the above analysis, it is inferred that surface topography plays a crucial role
in material osteoinductivity by modulating cell behaviors.
Overall, chemical composition, porous structure, and the surface micro-
and nanostructure of bioactive materials were regarded as playing important
roles in new bone regeneration. The relationships and interactions between
them are shown in Fig. 1.1.
1.1.2 Design of porous bioactive materials

1.1.2.1 Synthesis of initial nanopowder and precursor
Up to now, many methods have been developed for the synthesis of Ca-P
nanopowder and precursor: liquid precipitation [39e43], sol-gel processing
[44e48], emulsion technique [49e51], hydrothermal process [52e55], ultra-
sonic technique [56e58], mechanochemical method [59e61], template
method [62e66], microwave processing [67,68], and so on. Various mor-
phologies and structures of Ca-P nanopowder and precursor have been
synthesized by means of these methods including spherical, needlelike,
fibrous, nanorods, layer nanostructures, hollow nanospheres, and flowers.
However, each method for the synthesis of Ca-P nanopowder and precursor
has advantages and disadvantages. For example, Ca-P nanocrystals with ho-
mogenous morphologies can be easily synthesized by the sol-gel process, but
the process needs a high sintering temperature to decompose the organic
content. Similarly, biomimetic, needlelike/spherical nanocrystals, or nanorods
can be prepared using a simple liquid precipitation process, but the preparation
process is difficult to control, and the obtained particles easily aggregate.
As mentioned above, Ca-P powder or precursor with nanostructure can be
fabricated using many methods, and few products by means of corresponding
methods can be further considered for the fabrication of Ca-P bioceramics. On
the one hand, the yield of most methods is too low to supply fabricating Ca-P
bioceramics. For example, the hydrothermal process can synthesize high
crystallinity, small size, and good-shaped nanocrystals, but the yield of Ca-P
nanocrystals is quite low. In addition, the structures and morphologies of
Ca-P nanocrystals are important factors for determining the property of the
obtained ceramics. Those with plate, flower, and fiber morphologies are un-
desirable for the fabrication of porous Ca-P ceramics. Among them, liquid
precipitation seems to be most available to fabricate porous Ca-P bioceramics.
The well-dispersed, needlelike Ca-P nanoparticles have been synthesized by
liquid precipitation with the aid of dispersants (i.e., citric acid, polyethylene
glycol), which have been well employed in assembling porous Ca-P bio-
ceramics in our laboratory [36,39,69].
1.1.2.2 Molding of porous structure

To endow ceramics with bioactivity, the design of the scaffold porous structure
is vital. Porosity, pore size and shape, and interconnectivity are typical pa-
rameters for determining the biological and mechanical properties of the bone
scaffold. It is generally believed that porosity is necessary for cell migration,
attachment, and proliferation as wel as for neovascularization processes [20].
It is well known that natural bone has a multilevel pore structure (from
nanometer to micrometer thus to satisfy the growth of different tissue growth
[70e72]. Generally, a macropores range from 100 to 1000 mm facilitates the
ingrowth of bone tissue and blood vessels, and interconnected pores ranging
from 10 to 100 mm are beneficial for nutrient transport. Moreover, micropores
less than 10 mm favor protein adsorption and cell attachment [73e75].
Up to now, various methods have been developed to construct porous
structure, involving microsphere-sintering, gas-foaming, freeze-drying,
organic foam impregnation, and electrospinning (Table 1.1). Among them,
microsphere-sintering seems optimal because pore size and porosity can be
easily controlled via this method, but it is difficult to produce abundant mi-
cropores, so ceramics by this approach do not possess good bioactivity
including osteoinductivity [4]. One promising approach is an H2O2 gas-
foaming method that is favorable for producing ceramics with abundant mi-
cropores besides interconnecting macropores (shown in Fig. 1.2), and the
TABLE 1.1 Fabrication methods for three-dimensional porous ceramic

scaffolds.
Pore
diameter
Methods (mm) Advantages Disadvantages
Microsphere- 10e1000 High mechanical Lack of micropores;
sintering properties; controlled use of template
[76,77] pore size and porosity
Gas-foaming 100 Abundant micropores; Difficultly in
[4,78e80] e800; <100 interconnecting pores, controlling pore
low-cost structure
Freeze-drying 10e600 Biomimetic 3D porous Time-consuming
[81e83] structure
Organic foam 100e5000 Easily controlling, high Lack of micropores;
impregnation porosity low mechanical
[84e87] properties; use of
template
Electrospinning 0.1e50 High porosity; abundant Lack of macropores;
[88e90] micropores low mechanical
properties
3D printing [91 100e1000 Controlled pore size and Lack of micropores;
e93] porosity time-consuming
(A) (B)
FIGURE 1.2 Macro- and micropore structure of porous Ca-P ceramic fabricated by the gas-
foaming method.
process is low-cost, quick, and easy, whereas its shortcoming is difficulty in

controlling pore size and porosity [4,74]. It has proved to be the most chal-
lenging method to yield Ca-P ceramics with both interconnected macropores
and micropores that is effective in inducing bone formation.
(A) (B)
FIGURE 1.3 Morphology and structure of porous calcium phosphate ceramics fabricated by the
three-dimensional printing method.
In recent years, 3D printing methods have been widely developed and

employed to construct ceramic matrices with complex pore structures [92,94].
Special and complex shapes as well as internal channel networks mimicking
bony structures can be directly printed. The typical morphology and structure
of porous Ca-P ceramics fabricated by the 3D printing method are shown in
Fig. 1.3. Researchers can design and optimize implants for a target defect
based on anatomical information, which can be converted to a 3D data set
without a mold. Due to the capability of constructing complex shapes with
controlled porous structures, 3D printing is a very promising method for
fabricating bone graft scaffolds. However, the printing accuracy of the printer
must be improved [93]. At present, it is difficult to control the microstructure
under a micrometer scale by 3D printing. In addition, present routines include
the printing of scaffolds followed by sintering to yield ceramic scaffolds. Due
to the shrinkage of ceramics in sintering, it is difficult to acquire designed
scaffolds by direct 3D printing. Future research should develop novel proto-
typing methods to overcome these limitations with the goals of enhancing the
precision in micrometer control, mechanical properties, and bioactivity of
scaffolds. Our present work combines 3D printing with microwave sintering to
construct two-level hierarchical porous HA scaffolds, and in vivo results
demonstrate that the hierarchical macro-/microporous scaffold could induced
bone formation in canine intramuscular implantation [91].
1.1.2.3 Sintering technologies

The sintering process is necessary for fabricating bioceramics with certain
mechanical properties and ceramic structures. At the same time, some micro-
structures (i.e., crystal size, microporous structure) are generated by the sin-
tering process and result in varied physical, chemical, and biological
performance. Traditional sintering processes include muffle [4,95], hot pressure
[96,97], and vacuum sintering [98,99]. Sintering temperature and schedule are
the main factors for determining the performance of the obtained ceramics [95].
Each sintering process has varied advantages, disadvantages, and application

scopes (as listed in Table 1.2). As we all know, brittleness is one of the main
issues that restricts the clinic application of bioceramics, while high-temperature
sintering would increase ceramic mechanical strength.
However, higher temperature would result in a larger crystal size and
denser microstructure, which are regarded as adverse to bioactivity. The
typical SEM images of HA ceramic sintering via conventional muffle can be
seen in Fig. 1.4, with grain size on a submicro scale. Therefore, some new
sintering processes such as spark plasma [100e102], two-step [103,104], and
microwave sintering [4,39,105,106] have been employed to yield ceramics
with nanocrystals, and the increased micropores show potential for optimizing
ceramic bioactivity. Among these processes, microwave sintering seems to be
the most attractive technique for fabricating Ca-P nanoceramics. The principle
of microwave sintering is based on dielectric dissipation of the electromag-
netic waves in dielectric ceramics. Compared with conventional muffle
sintering, microwave sintering provides a highly efficient, rapid, and low-
energy-cost process for nanoceramic fabrication (Table 1.2). Generally, the
TABLE 1.2 Advantages and disadvantages of different ceramic sintering

processes.
Methods Advantages Disadvantages

Muffle sintering Cheap device; high yield; Time- and energy-consuming;
[4,95] suitable for conventional unsuitable for nanoceramic sintering
and large size of ceramic
sintering
Hot pressure Suitable for conventional Low yield; time- and energy-
sintering and dense ceramic consuming; unsuitable for
[96,97] sintering; high mechanical nanoceramic sintering
strength
Vacuum Suitable for conventional Special equipment, time- and
sintering and large size of ceramic energy-consuming; unsuitable for
[98,99] sintering; high yield nanoceramic sintering
Spark plasma Rapid process; low energy Expensive devices; low yield;
sintering [100 and time cost; suitable for difficult for large size of ceramic
e102] nanoceramic sintering sintering
Two-step Inexpensive device Time- and energy-consuming;
sintering difficult for nanoceramic sintering
[103,104]
Microwave Rapid process; low energy Expensive devices; different for large
sintering and time cost; suitable for size of ceramic sintering
[4,39,105,106] nanoceramic sintering
FIGURE 1.4 SEM images of HA ceramics with submicrograin and nanograin sizes.
heating efficiency of Ca-P ceramics by microwave sintering is not high, due to the
low dielectric absorption of Ca-P materials. Some researchers have attempted to
combine radiant heating with microwave heating to increase heating efficiency,
and thermal gradients can be overcome to some extent [107]. Our previous
experiment modified microwave sintering devices by employing active carbon as
a radiant material and discovered that microwave sintering parameters (e.g.,
sintering temperature, heating rate, and holding time) were quite important
in determining the grain sizes and microstructures of the obtained Ca-P
nanoceramics (typical SEM images can be observed in Fig. 1.4) [4,36].
1.1.2.4 Surface modification methods

Material surface with microroughness, micro- and nanostructured topogra-
phies, and patterned structured surfaces can significantly affect the bioactivity
and biological responses of implants and subsequently can stimulate tissue
regeneration [108e111]. In particular, recent studies have confirmed that
biomaterials with roughness surface can correctly command cellular behaviors
(i.e., cell adhesion, morphology, spreading, proliferation, migration, differen-
tiation, and so on) compared with a flat surface [112e116]. Recently, some
patterning methods, such as lithography [117,118], mechanical punching and
stenciling [119], self-assembly [120,121], and chemical etching [122], have
been developed to construct various patterns (i.e., parallel ridges and micro-
grooves [113], pits or pillars [123], dots [112], and arrays [124], http://pubs.
rsc.org/en/content/articlehtml/2014/tb/c4tb01838a - cit36). Generally, these
methods have been widely fabricated on the substrates of polymers, semi-
conductors, and metals to enhance their bioactivity and tissue-regeneration
capacity. However, it is generally difficult to directly construct the patterns
on the substrates of ceramics due to the natural brittleness of ceramics. The
most commonly used methods for fabricating patterns on ceramic substrates
include direct laser interference patterning (DLIP) [125], micromachining
technology [126], and direct writing patterning [127]. Berger et al.
(A) (B)
(C) (D)
FIGURE 1.5 SEM images of porous BCP ceramics with HA nanocrystalline coating.
successfully employed the DLIP method to fabricate periodic line- and cross-
like patterns on the surface of HA ceramics [125]. Microgrooves with a
minimum width of 100 mm on zirconia and HA ceramics were well con-
structed by the micromachining method in the research of Holthaus et al.
[126]. Our previous work [128] fabricated orderly microgroove patterns on
HA dense ceramics by transferring patterns from an aluminum alloy template
and observed that the cells were oriented along the direction of groove, and
cell orientation angles decreased with decreases in groove width. Surface
coating is also a widely used method to modify the implant surface. In our
recent work, we combined the H2O2 foaming method with surface-coating
technology to construct porous BCP ceramics with an HA nanocrystalline
coating (shown in Fig. 1.5). The results showed that BCP ceramics with an HA
nanocrystalline coating showed enhanced bioactivity compared with that of
uncoated ones [129].
1.1.3 Main challenges and prospects

1.1.3.1 Main challenges of bioactive materials
Due to the capacity for forming bone bonds, most existing bioceramics are
bioactive and have been successfully applied in clinical settings. However, as
requirements for tissue regeneration grow, traditional bioceramics are far from
satisfying and need further optimization to endow them with tissue-

regenerative abilities. Most challenges lie in the following three aspects.
For one thing, the brittleness and low resistance to fatigue of bioactive
ceramics restrict usage to bone defect filling, while little is used in repairing
large bone defects or load-bearing repair [130e133]. Many efforts have been
made to enhance the mechanical properties of ceramics [107,134e136]. One
commonly employed method is fabricating composite scaffolds. It is well
known that natural bone is composed of organic collagen, inorganic mineral,
proteins, and cells [130,137]. Therefore, many ceramic-based composite have
been developed, including composites with natural polymers (such as
collagen, hyaluronic acid, coral and chitosan) and composites with synthetic
polymers including polyglycolic acid (PGA), polylactic acid (PLA) and their
copolymers (PLGA), polymethyl methacrylate, and polyethylene
[70,138e140]. These composites generally show better mechanical properties
than those of the ceramics themselves. The other popular route is developing a
nanoceramic scaffold. Much research has certified that nanomaterials have
strength and toughness superior to those of conventional materials [130]. For
instance, HA nanoceramics prepared by selective laser sintering showed
outstanding mechanical properties and bioactivity for inducing bone regen-
eration [141]. Although these attempts have improved the mechanical prop-
erties to some extent, drawbacks remain, such as the toxicity of degradation
products, complexity of the fabrication process, and reduced bioactivity as
well as unsatisfied strength for load-bearing repair. With increasing interest in
regenerative medicine, researchers believe that improvements in material
bioactivity to achieve rapid tissue regeneration may be the essential solution
for solving the problem of the weak mechanical properties of ceramic
implants.
The design of biodegradable ceramics is another challenge in adapting
their degradation kinetics to the speed of new tissue formation [142]. On the
basic point of regenerative medicine, implants ideally should be degraded
gradually and ultimately replaced by new tissue. Generally, the degradation
rate of ceramics could be partly adjusted by phase composition [143,144]. For
example, a composite mixture with an optimum b-TCP/HA phase ratio could
achieve suitable degradability [73,145]. Simultaneously, ceramic degradation
would release soluble ions (such as Ca2þ, PO3 4þ
4 , and Si ), which might favor
bone formation and the generation of extraporosity as a consequence of
dissolution, in turn facilitating biological fixation of the implant. Combination
with a degradable polymer is another efficient approach to adjust the degra-
dation rate of bioceramics [138]. The most frequently used biodegradable
polymer materials include PLA, PGA, and PLGA. Because the degradation
rate of implants should match that of new tissue regeneration, enhancing
bioactivity to induce tissue regeneration should be carefully considered when
designing degradable bioceramics.
In fact, current biomaterials still have relatively low bioactivity compared

with that of natural bones. As previously mentioned, improvement of both
mechanical strength and degradation properties is far from satisfying, and the
ultimate solution might depend on fast and massive tissue formation to thus
rebuild the tissue biofunction of regenerated tissue. Therefore, the improve-
ment of bioactivity is the fundamental way to overcome these challenges and
is the eternal topic when designing bioceramics.
1.1.3.2 Enhancing bioactivity and mechanical property methods

1.1.3.2.1 Bonelike apatite formation
It is well known that a layer of bonelike apatite forms on the surface of implants
play an important role in deterring the bone regeneration that follows [146]. The
bonelike apatite is composed of calcium hydroxyl carbonate apatite [147e149],
which is similar to the composition and structure of natural bone minerals
[1,19,150]. The bonelike apatite-forming ability has become a direct criterion
for evaluating the bioactivity of a kind of biomaterial [148,151e153]. Various
studies have certified that many kinds of bioactive materials could induce the
bonelike apatite formation in vitro, and implants with the bonelike layer showed
strong bone formation in the following animal experiments [150,154].
In fact, almost all Ca-P ceramics can form a layer of apatite due to the
dissolution and reprecipitation process in the aqueous system, and the bonelike
apatite formation ability is generally a positive correction with osteoinduc-
tivity [150,155]. Our previous works have demonstrated that the presence of
protein molecules in the bonelike apatite changed the surface microstructure
compared with that without protein molecules and showed higher osteoin-
ductivity [155,156]. In our previous works, we adopted a simulated body fluid
(SBF) immersing method to enhance the bioactivity of polyetherketoneketone
(PEKK) materials. Compared with PEKK alone, the obtained materials
elevated osteogenic gene expression [157]. Furthermore, the modified PEKK
materials had good osteointegration properties after implanting in the femoral
condyle defects of rat models [158].
1.1.3.2.2 Nanoscale topography

It is known that bone apatite consists of nanosized HA crystals. The optimal
approach to fabricating artificial bone grafts is biomimetics. However, current
porous Ca-P ceramics are of microscale grain size, which could decrease the
bioactivity of porous Ca-P ceramics to some extent [1,4,159]. On the point of
biomimetics, the bioactivity of Ca-P ceramics should improve remarkably
when grain size falls into the nanoscale range. Many previous studies have
certified that biomaterials with nanoscale structures could promote bone-
related cell adhesion, proliferation, and other beneficial behaviors
[39,160e164]. Recently, porous Ca-P nanoceramics were successfully
fabricated by modified microwave sintering [4,39]. The obtained nano-

ceramics could absorb more bone-related proteins and promote osteogenic
differentiation of BMSCs, thereby resulting in higher osteoinductivity and
bone regeneration than with conventional ceramics in animal experiments.
1.1.3.2.3 Whisker reinforcement

In recent years, structure-reinforced ceramic matrix composites have become a
hot spot in material science and technology research, especially for whisker-
reinforced ceramic matrix composites. Many studies suggest that adding
whiskers to ceramic matrix can contribute to improved ceramic toughness,
elastic modulus, hardness, and compressive strength [165,166]. Generally,
increasing whisker contents can improve ceramic mechanical properties, but
the agglomerate of excess whiskers leads to stress concentration and weak
mechanical properties. As a result, the current prepared HA whisker-reinforced
biphasic calcium phosphate (BCP) ceramic composite has a limited
improvement in mechanical properties. Our present study found that porous
BCP ceramics could transform into calcium-deficient HA whisker (HAw)
skeleton in hydrothermal environment [167], and the ceramics have excellent
mechanical properties (Fig. 1.6). HAw-reinforced BCP ceramic composites
FIGURE 1.6 Comparisons of the morphologies and mechanical properties of biphasic calcium
phosphate, hydroxyapatite whisker skeleton, and RBCP ceramics.
were filled with sufficient and well-distributed whiskers, and the obtained
samples had good biocompatibility and bioactivity. Further intramuscular and
femoral implantation certified that the prepared ceramics had significant
enhanced mechanical properties, excellent osteoinductivity, and good bone
repair capacity [168].
1.1.3.2.4 Trace ion doping

It is known that natural bone is a dynamic and vascularized tissue with the
ability to remodel by regulating cell behaviors, secreting growth factors and
hormones, and changing stress actions [169e171]. During this process, some
trace elements such as calcium (Ca) [169,172,173], phosphorous (P) [174],
strontium (Sr) [175e177], Si [11,178], and zinc (Zn) [170,179] as well as
vanadium (V) [171,180,181], boron (B) [182,183], magnesium (Mg)
[184e186], and cobalt (Co) [181,187,188] are known to be involved in bone
metabolism and play an important role in the angiogenesis, growth, and
regeneration of bone tissue [189e191]. In the works of Chang J et al. [192],
bioactive Sr2MgSi2O7 (SMS) ceramic coatings on Tie6Ale4V with Sr2þ,
Mg2þ, and Si4þ doping were successfully prepared by the plasma-spray
coating method, which could also inhibit osteoclastogenesis while maintain-
ing good osteogenesis-inducing capacity.
Overall, the development of regenerative medicine provides a prospective
approach for bone repair. It is quite important to further optimize the physi-
cochemical properties in order to fully mimic the architectural structures of
natural bone. Bioactive materials with certain compositions and structures
possess the ability to form new bone by inducing differentiation of various
stem cells, which are receiving increasing attention due to their excellent
osteoinductivity. Although the mechanism of osteoinductivity is still not fully
understood, the main material characteristics, fabricating processes, and
optimizing methods relevant for osteoinductivity have been discussed herein.
Based on these descriptions, the bioactivity of porous biomaterials can be
further enhanced by optimized design of the material itself, which will help us
gain a deeper understanding of the mechanism of bioactivity and osteoinduct
ivity.
References
[1] Z. Wang, et al., Applications of calcium phosphate nanoparticles in porous hard tissue
engineering scaffolds, Nano 7 (04) (2012) 1230004.
[2] J. Wang, et al., Effect of phase composition on protein adsorption and osteoinduction of
porous calcium phosphate ceramics in mice, J. Biomed. Mater. Res. A 102 (12) (2014)
4234e4243.
[3] A.M.C. Barradas, et al., Osteoinductive biomaterials: current knowledge of properties,
experimental models and biological mechanisms, Eur. Cells Mater. 21 (2011) 407e429.
[4] T.S. Xiangfeng Li, X. Chen, M. Wang, X. Yang, Y. Xiao, X. Zhang, Osteoinductivity of
porous biphasic calcium phosphate ceramic spheres with nanocrystalline and their efficacy
in guiding bone regeneration, ACS Appl. Mater. Interfaces 11 (4) (2019) 3722e3736.
[5] H. Yuan, et al., Bone formation induced by calcium phosphate ceramics in soft tissue of
dogs: a comparative study between porous a-TCP and b-TCP, J. Mater. Sci. Mater. Med. 12
(1) (2001) 7e13.
[6] S. Samavedi, A.R. Whittington, A.S. Goldstein, Calcium phosphate ceramics in bone tissue
engineering: a review of properties and their influence on cell behavior, Acta Biomaterialia
9 (9) (2013) 8037e8045.
[7] H. Yuan, et al., A comparison of the osteoinductive potential of two calcium phosphate
ceramics implanted intramuscularly in goats, J. Mater. Sci. Mater. Med. 13 (12) (2002)
1271e1275.
[8] X. Li, et al., Stabilization of Ca-deficient hydroxyapatite in biphasic calcium phosphate
ceramics by adding alginate to enhance their biological performances, J. Mater. Chem. B 6
(1) (2017).
[9] C. Wu, J. Chang, A review of bioactive silicate ceramics, Biomed. Mater. 8 (3) (2013)
032001.
[10] K. Schwarz, A bound form of silicon in glycosaminoglycans and polyuronides, Proc. Natl.
Acad. Sci. 70 (5) (1973) 1608e1612.
[11] E.M. Carlisle, Silicon: a possible factor in bone calcification, Science 167 (3916) (1970)
279e280.
[12] Q. Liu, et al., A comparative study of proliferation and osteogenic differentiation of
adipose-derived stem cells on akermanite and b-TCP ceramics, Biomaterials 29 (36)
(2008) 4792e4799.
[13] L. Xia, et al., Proliferation and osteogenic differentiation of human periodontal ligament
cells on akermanite and b-TCP bioceramics, Eur. Cells Mater. 22 (68) (2011) e82.
[14] Y. Huang, et al., In vitro and in vivo evaluation of akermanite bioceramics for bone
regeneration, Biomaterials 30 (28) (2009) 5041e5048.
[15] J.A. Juhasz, S.M. Best, Bioactive ceramics: processing, structures and properties, J. Mater.
Sci. 47 (2) (2012) 610e624.
[16] J.R. Jones, 3 e bioactive ceramics and glasses, in: Tissue Engineering Using Ceramics &
Polymers, 2007, pp. 52e71.
[17] C.G. Pantano Jr., A.E. Clark Jr., L.L. Hench, Multilayer corrosion films on bioglass sur-
faces, J. Am. Ceram. Soc. 57 (9) (1974) 412e413.
[18] X. Zhang, et al., A calcium phosphate, bioceramics with osteoinduction, in: The 4th World
Biomaterials Congress, April. 1992.
[19] H. Yuan, et al., Osteoinduction by calcium phosphate biomaterials, J. Mater. Sci. Mater.
Med. 9 (12) (1998) 723e726.
[20] Y. Chen, et al., Enhanced effect of b-tricalcium phosphate phase on neovascularization of
porous calcium phosphate ceramics: in vitro and in vivo evidence, Acta Biomater. 11
(2015) 435e448.
[21] Z. Yang, et al., Osteogenesis in extraskeletally implanted porous calcium phosphate ce-
ramics: variability among different kinds of animals, Biomaterials 17 (22) (1996)
2131e2137.
[22] H. Yamasaki, H. Sakai, Osteogenic response to porous hydroxyapatite ceramics under the
skin of dogs, Biomaterials 13 (5) (1992) 308e312.
[23] C. Klein, et al., Osseous substance formation induced in porous calcium phosphate ce-
ramics in soft tissues, Biomaterials 15 (1) (1994) 31e34.
[24] P. Habibovic, et al., Osteoconduction and osteoinduction of low-temperature 3D printed

bioceramic implants, Biomaterials 29 (7) (2008) 944e953.
[25] X. Zhu, et al., Effect of phase composition and microstructure of calcium phosphate
ceramic particles on protein adsorption, Acta Biomaterialia 6 (4) (2010) 1536e1541.
[26] X. Zhu, et al., Effect of surface structure on protein adsorption to biphasic calcium-
phosphate ceramics in vitro and in vivo, Acta Biomaterialia 5 (4) (2009) 1311e1318.
[27] G. Dunn, J. Heath, A new hypothesis of contact guidance in tissue cells, Exp. Cell Res. 101
(1) (1976) 1e14.
[28] Y.A. Rovensky, I. Slavnaja, J.M. Vasiliev, Behaviour of fibroblast-like cells on grooved
surfaces, Exp. Cell Res. 65 (1) (1971) 193e201.
[29] D.D. Deligianni, et al., Effect of surface roughness of hydroxyapatite on human bone
marrow cell adhesion, proliferation, differentiation and detachment strength, Biomaterials
22 (1) (2000) 87e96.
[30] A.L. Rosa, M.M. Beloti, R. van Noort, Osteoblastic differentiation of cultured rat bone
marrow cells on hydroxyapatite with different surface topography, Dent. Mater. 19 (8)
(2003) 768e772.
[31] E.K. Yim, S.W. Pang, K.W. Leong, Synthetic nanostructures inducing differentiation of
human mesenchymal stem cells into neuronal lineage, Exp. Cell Res. 313 (9) (2007)
1820e1829.
[32] A. Chaubey, et al., Surface patterning: tool to modulate stem cell differentiation in an
adipose system, J. Biomed. Mater. Res. B Appl. Biomater. 84 (1) (2008) 70e78.
[33] T. Tzvetkova-Chevolleau, et al., The motility of normal and cancer cells in response to the
combined influence of the substrate rigidity and anisotropic microstructure, Biomaterials
29 (10) (2008) 1541e1551.
[34] M.J. Dalby, et al., The control of human mesenchymal cell differentiation using nanoscale
symmetry and disorder, Nat. Mater. 6 (12) (2007) 997e1003.
[35] R.J. McMurray, et al., Nanoscale surfaces for the long-term maintenance of mesenchymal
stem cell phenotype and multipotency, Nat. Mater. 10 (8) (2011) 637e644.
[36] Y. Hong, et al., Fabrication, biological effects, and medical applications of calcium
phosphate nanoceramics, Mater. Sci. Eng. R Rep. 70 (3e6) (2010) 225e242.
[37] X.N. Chen, et al., Rat bone marrow cell responses on the surface of hydroxyapatite with
different topography, in: Key Engineering Materials, Trans Tech Publ, 2008.
[38] Z. Wang, et al., Fabrication of micro-grooved patterns on hydroxyapatite ceramics and
observation of earlier response of osteoblasts to the patterns, Wuji Cailiao Xuebao 28 (1)
(2013) 51e57.
[39] B. Li, et al., Fabrication and cellular biocompatibility of porous carbonated biphasic cal-
cium phosphate ceramics with a nanostructure, Acta Biomater. 5 (1) (2009) 134e143.
[40] V.M. Rusu, et al., Size-controlled hydroxyapatite nanoparticles as self-organized
organiceinorganic composite materials, Biomaterials 26 (2005) 5414e5426.
[41] P.N. Kumta, et al., Nanostructured calcium phosphates for biomedical applications: novel
synthesis and characterization, Acta Biomater. 1 (1) (2005) 65e83.
[42] R. Gonzalez-Mcquire, et al., Synthesis and characterization of amino acid-functionalized
hydroxyapatite nanorods, J. Mater. Chem. 14 (14) (2004) 2277e2281.
[43] Y. Zhai, F.Z. Cui, Recombinant human-like collagen directed growth of hydroxyapatite
nanocrystals, J. Cryst. Growth 291 (1) (2006) 202e206.
[44] D.M. Liu, T. Troczynski, W.J. Tseng, Aging effect on the phase evolution of water-based
sol-gel hydroxyapatite, Biomaterials 23 (4) (2002) 1227e1236.
[45] A. Jillavenkatesa, D.T. Hoelzer, R.A. Condrate, An electron microscopy study of the
formation of hydroxyapatite through sol-gel processing, J. Mater. Sci. 34 (19) (1999)
4821e4830.
[46] I.S. Kim, P.N. Kumta, Solegel synthesis and characterization of nanostructured hy-
droxyapatite powder, Mater. Sci. Eng., B 111 (2) (2004) 232e236.
[47] T.A. Kuriakose, et al., Synthesis of stoichiometric nano crystalline hydroxyapatite by
ethanol-based solegel technique at low temperature, J. Cryst. Growth 263 (1e4) (2004)
517e523.
[48] A. Bigi, E. Boanini, K. Rubini, Hydroxyapatite gels and nanocrystals prepared through a
solegel process, J. Solid State Chem. 177 (9) (2004) 3092e3098.
[49] G.K. Lim, et al., Nanosized hydroxyapatite powders from microemulsions and emulsions
stabilized by a biodegradable surfactant, J. Mater. Chem. 9 (7) (1999) 1635e1639.
[50] S.B. And, S.K. Saha, Synthesis and characterization of hydroxyapatite nanopowders by
emulsion technique, Chem. Mater. 15 (23) (2003) 4464e4469.
[51] K. Sato, et al., Agglomeration control of hydroxyapatite nano-crystals grown in phase-
separated microenvironments, J. Mater. Sci. 41 (17) (2006) 5424e5428.
[52] R.E. Riman, et al., Solution synthesis of hydroxyapatite designer particulates, Solid State
Ion. 151 (1) (2002) 393e402.
[53] A.F. Lemos, et al., Hydroxyapatite nano-powders produced hydrothermally from nacreous
material, J. Eur. Ceram. Soc. 26 (16) (2006) 3639e3646.
[54] A.A. Chaudhry, et al., Instant nano-hydroxyapatite: a continuous and rapid hydrothermal
synthesis, Chem. Commun. 2286e2288 (21) (2006) 2286e2288.
[55] Z.H. Zhou, et al., Controllable synthesis of hydroxyapatite nanocrystals via a dendrimer-
assisted hydrothermal process, Mater. Res. Bull. 42 (9) (2007) 1611e1618.
[56] K.S. Suslick, Sonochemistry, Science 247 (4949) (1990) 1439e1445.
[57] E.B. Flint, K.S. Suslick, The temperature of cavitation, Science 253 (5026) (1991)
1397e1399.
[58] C.J. Ren, et al., Synthesis of hydroxyapatite nanoparticles in ultrasonic precipitation,
Ceram. Int. 31 (8) (2005) 1041e1044.
[59] C. Shu, et al., Synthesis of carbonated hydroxyapatite nanofibers by mechanochemical
methods, Ceram. Int. 31 (1) (2005) 135e138.
[60] J.,C.A., et al., Mechanochemical synthesis of nanocrystalline carbonate-substituted hy-
droxyapatite, Opt. Mater. 27 (7) (2005) 1281e1285.
[61] S. Nakamura, T. Isobe, M. Senna, Hydroxyapatite nano sol prepared via A mechano-
chemical route, J. Nanoparticle Res. 3 (1) (2001) 57e61.
[62] Y. Zhang, et al., Oriented nano-structured hydroxyapatite from the template, Chem. Phys.
Lett. 376 (3) (2003) 493e497.
[63] Z. Yang, et al., Template synthesis of highly ordered hydroxyapatite nanowire arrays,
J. Mater. Sci. 40 (5) (2005) 1121e1125.
[64] J. Yao, et al., Hydroxyapatite nanostructure material derived using cationic surfactant as a
template, J. Mater. Chem. 13 (12) (2003) 3053e3057.
[65] Y. Wu, S. Bose, Nanocrystalline hydroxyapatite: micelle templated synthesis and char-
acterization, Langmuir 21 (8) (2005) 3232e3234.
[66] L. Chao, X. Ji, G. Cheng, Template synthesis and characterization of highly ordered
q
lamellar hydroxyapatite , Appl. Surf. Sci. 253 (16) (2007) 6840e6843.
[67] A. Siddharthan, S.K. Seshadri, T.S.S. Kumar, Rapid synthesis of calcium deficient hy-
droxyapatite nanoparticles by microwave irradiation, Trends Biomater. Artif. Organs 18 (2)
(2005) 110e113.
[68] J. Liu, et al., Rapid formation of hydroxyapatite nanostructures by microwave irradiation,

Chem. Phys. Lett. 396 (4) (2004) 429e432.
[69] Z. Wang, et al., Applications of calcium phosphate nanoparticles in porous hard tissue
engineering scaffolds, Nano 07 (04) (2012), 1230004 1e18.
[70] M. Schieker, et al., Biomaterials as scaffold for bone tissue engineering, Eur. J. Trauma 32
(2) (2006) 114e124.
[71] C.H.G. Price, Book review Bones and joints (monographs in pathologydNo. 17), in:
V. AckermanL, J. SpjutH, R. AbellM (Eds.), Xi þ 349, 190 Illus, 1976 (Baltimore, The
Williams and Wilkins Company), £27$00. British Journal of Radiology, 1977. 50(593): pp.
311e311.
[72] S.W. And, H.D. Wagner, The material bone: structure mechanical function relations, Annu.
Rev. Mater. Res. 28 (1) (2003) 271e298.
[73] J. Wang, et al., Effect of phase composition on protein adsorption and osteoinduction of
porous calcium phosphate ceramics in mice, J. Biomed. Mater. Res. A 102 (12) (2014)
4234e4243.
[74] X. Li, et al., Gelatinizing technology combined with gas foaming to fabricate porous
spherical hydroxyapatite bioceramic granules, Mater. Lett. 185 (2016) 428e431.
[75] H. Chen, et al., Fabrication of porous titanium scaffolds by stack sintering of microporous
titanium spheres produced with centrifugal granulation technology, Mater. Sci. Eng. C 43
(2014) 182e188.
[76] M. Descamps, et al., Synthesis of macroporous b-tricalcium phosphate with controlled
porous architectural, Ceram. Int. 34 (5) (2008) 1131e1137.
[77] M. Descamps, et al., Manufacture of macroporous b-tricalcium phosphate bioceramics,
J. Eur. Ceram. Soc. 28 (1) (2008) 149e157.
[78] E. Ryshkewitch, Compression strength of porous sintered alumina and zirconia, J. Am.
Ceram. Soc. 36 (2) (2006) 65e68.
[79] N.O. Engin, A.C. Tas, Manufacture of macroporous calcium hydroxyapatite bioceramics,
J. Eur. Ceram. Soc. 19 (13e14) (1999) 2569e2572.
[80] I.H. Aritaa, et al., Chemistry and sintering behaviour of thin hydroxyapatite ceramics with
controlled porosity, Biomaterials 16 (5) (1995) 403e408.
[81] Q. Fu, et al., Freeze-spray deposition of layered alumina/zirconia composites, Mater. Sci.
Eng., B 161 (1e3) (2009) 120e124.
[82] Q. Fu, et al., Freeze casting of porous hydroxyapatite scaffolds. I. Processing and general
microstructure, J. Biomed. Mater. Res. B Appl. Biomater. 86 (1) (2008) 125e135.
[83] S. Deville, E. Saiz, A.P. Tomsia, Freeze casting of hydroxyapatite scaffolds for bone tissue
engineering, Biomaterials 27 (32) (2006) 5480e5489.
[84] B. Liu, et al., Porous bioceramics reinforced by coating gelatin, J. Mater. Sci. Mater. Med.
19 (3) (2008) 1203e1207.
[85] X. Yang, Z. Wang, Synthesis of biphasic ceramics of hydroxyapatite and b-tricalcium
phosphate with controlled phase content and porosity, J. Mater. Chem. 8 (10) (1998)
2233e2237.
[86] J. Tian, J. Tian, Preparation of porous hydroxyapatite, J. Mater. Sci. 36 (12) (2001)
3061e3066.
[87] H.X. Peng, et al., Microstructure of ceramic foams, J. Eur. Ceram. Soc. 20 (7) (2000)
807e813.
[88] C. Erisken, D.M. Kalyon, H. Wang, Functionally graded electrospun polycaprolactone and
b-tricalcium phosphate nanocomposites for tissue engineering applications, Biomaterials
29 (30) (2008) 4065e4073.
[89] Y. Hong, et al., Synthesis using electrospinning and stabilization of single layer macro-
porous films and fibrous networks of poly(vinyl alcohol), J. Membr. Sci. 276 (1e2) (2006)
1e7.
[90] Y. Hong, H. Fan, X. Zhang, Synthesis and protein adsorption of hierarchical nanoporous
ultrathin fibers, J. Phys. Chem. B 113 (17) (2009) 5837e5842.
[91] X. Pei, et al., Creating hierarchical porosity hydroxyapatite scaffold with osteoinduction by
three-dimensional printing and microwave sintering, Biofabrication 9 (4) (2017).
[92] H.N. Chia, B.M. Wu, Recent advances in 3D printing of biomaterials, J. Biol. Eng. 9 (1)
(2015) 4.
[93] M. Guvendiren, et al., Designing biomaterials for 3D printing, ACS Biomater. Sci. Eng. 2
(10) (2016) 1679.
[94] C. Bergmann, et al., 3D printing of bone substitute implants using calcium phosphate and
bioactive glasses, J. Eur. Ceram. Soc. 30 (12) (2010) 2563e2567.
[95] E. Champion, Sintering of calcium phosphate bioceramics, Acta Biomater. 9 (4) (2013)
5855e5875.
[96] P. Li, I.-W. Chen, J.E. Penner-Hahn, X-ray-absorption studies of zirconia polymorphs. I.
Characteristic local structures, Phys. Rev. B 48 (14) (1993) 10063.
[97] D. Veljovic, et al., Processing of dense nanostructured HAP ceramics by sintering and hot
pressing, Ceram. Int. 35 (4) (2009) 1407e1413.
[98] P. Ducheyne, et al., Calcium phosphate ceramic coatings on porous titanium: effect of
structure and composition on electrophoretic deposition, vacuum sintering and in vitro
dissolution, Biomaterials 11 (4) (1990) 244e254.
[99] P.E. Wang, T. Chaki, Sintering behaviour and mechanical properties of hydroxyapatite and
dicalcium phosphate, J. Mater. Sci. Mater. Med. 4 (2) (1993) 150e158.
[100] Y. Gu, et al., Spark plasma sintering of hydroxyapatite powders, Biomaterials 23 (1) (2002)
37e43.
[101] J. Xu, et al., Radio frequency (rf) plasma spheroidized HA powders: powder character-
ization and spark plasma sintering behavior, Biomaterials 26 (15) (2005) 2197e2207.
[102] W. Li, L. Gao, Fabrication of HApeZrO 2 (3Y) nano-composite by SPS, Biomaterials 24
(6) (2003) 937e940.
[103] I.-W. Chen, X.-H. Wang, Sintering dense nanocrystalline ceramics without final-stage
grain growth, Nature 404 (6774) (2000) 168e171.
[104] K. Lin, L. Chen, J. Chang, Fabrication of dense hydroxyapatite nanobioceramics with
enhanced mechanical properties via two-step sintering process, Int. J. Appl. Ceram.
Technol. 9 (3) (2012) 479e485.
[105] X. Wang, et al., Fabrication and characterization of porous hydroxyapatite/b-tricalcium
phosphate ceramics by microwave sintering, Mater. Lett. 60 (4) (2006) 455e458.
[106] N. Rameshbabu, K.P. Rao, Microwave synthesis, characterization and in-vitro evaluation
of nanostructured biphasic calcium phosphates, Curr. Appl. Phys. 9 (1) (2009) S29eS31.
[107] S. Ramesh, et al., Consolidation of nanocrystalline hydroxyapatite powder, Sci. Technol.
Adv. Mater. 8 (1) (2007) 124e130.
[108] K. Lin, et al., Tailoring the nanostructured surfaces of hydroxyapatite bioceramics to
promote protein adsorption, osteoblast growth, and osteogenic differentiation, Appl. Mater.
Inter. 5 (16) (2013) 8008e8017.
[109] L. Xia, et al., Effect of nano-structured bioceramic surface on osteogenic differentiation of
adipose derived stem cells, Biomaterials 35 (30) (2014) 8514e8527.
q
[110] F. Gentile, et al., Cells preferentially grow on rough substrates , Biomaterials 31 (28)
(2010) 7205e7212.
[111] J.W. Park, et al., Enhanced osteoblast response to an equal channel angular pressing-
processed pure titanium substrate with microrough surface topography, Acta Biomater. 5
(8) (2009) 3272e3280.
[112] M.S. Niepel, et al., Nanoscaled surface patterns influence adhesion and growth of human
dermal fibroblasts, Langmuir 29 (43) (2013) 13278e13290.
[113] X. Shi, et al., Periosteum-mimetic structures made from freestanding microgrooved
nanosheets, Adv. Mater. 26 (20) (2014) 3290e3296.
[114] N.M. Alves, et al., Controlling cell behavior through the design of polymer surfaces, Small
6 (20) (2010) 2208e2220.
[115] L.E. Mcnamara, et al., The role of microtopography in cellular mechanotransduction,
Biomaterials 33 (10) (2012) 2835e2847.
[116] X. Wang, et al., Influence of cell protrusion and spreading on adipogenic differentiation of
mesenchymal stem cells on micropatterned surfaces, Soft Matter 9 (16) (2013)
4160e4166.
[117] H.Y. Chen, et al., Substrate-independent dip-pen nanolithography based on reactive
coatings, J. Am. Chem. Soc. 132 (51) (2010) 18023e18025.
[118] R. Fishler, et al., Mixed alkanethiol monolayers on submicrometric gold patterns: a
controlled platform for studying cell-ligand interactions, Nano Lett. 12 (9) (2012) 4992.
[119] D. Wright, et al., Reusable, reversibly sealable parylene membranes for cell and protein
patterning, J. Biomed. Mater. Res. A 85A (2) (2010) 530e538.
[120] X. Ye, L. Qi, Two-dimensionally patterned nanostructures based on monolayer colloidal
crystals: controllable fabrication, assembly, and applications, Nano Today 6 (6) (2011)
608e631.
[121] A. Scheffel, et al., From the Cover: nanopatterned protein microrings from a diatom that
direct silica morphogenesis, Proc. Natl. Acad. Sci. U.S.A. 108 (8) (2011) 3175.
[122] H.W. Chien, W.B. Tsai, Fabrication of tunable micropatterned substrates for cell patterning
via microcontact printing of polydopamine with poly(ethylene imine)-grafted copolymers,
Acta Biomater. 8 (10) (2012) 3678e3686.
[123] C. Yu, et al., Modulating particle adhesion with micro-patterned surfaces, ACS Appl.
Mater. Interfaces 6 (11) (2014) 8199e8207.
[124] A.M. Ross, J. Lahann, Surface engineering the cellular microenvironment via patterning
and gradients, J. Polym. Sci. B Polym. Phys. 51 (10) (2013) 775e794.
[125] J. Berger, et al., Ultraviolet laser interference patterning of hydroxyapatite surfaces, Appl.
Surf. Sci. 257 (7) (2011) 3081e3087.
[126] M.G. Holthaus, et al., Micromachining of ceramic surfaces: hydroxyapatite and zirconia,
J. Mater. Process. Technol. 212 (3) (2012) 614e624.
[127] D.M. Chun, et al., Nano-particle deposition system (NPDS): low energy solvent-free dry
spray process for direct patterning of metals and ceramics at room temperature, Int. J.
Precis. Eng. Manuf. 13 (7) (2012) 1107e1112.
[128] Z. Wang, et al., Fabrication of micro-grooved patterns on hydroxyapatite ceramics and
observation of earlier response of osteoblasts to the patterns, J. Inorg. Mater. 28 (1) (2013)
51e57.
[129] J. Wang, et al., Fabrication and preliminary biological evaluation of a highly porous
biphasic calcium phosphate scaffold with nano-hydroxyapatite surface coating, Ceram. Int.
44 (2) (2018) 1304e1311.
[130] C. Gao, et al., Current progress in bioactive ceramic scaffolds for bone repair and
regeneration, Int. J. Mol. Sci. 15 (3) (2014) 4714e4732.
[131] S.-S. Kim, et al., Poly (lactide-co-glycolide)/hydroxyapatite composite scaffolds for bone
tissue engineering, Biomaterials 27 (8) (2006) 1399e1409.
[132] I. Thompson, L. Hench, Mechanical properties of bioactive glasses, glass-ceramics and
composites, Proc. Inst. Mech. Eng. H J. Eng. Med. 212 (2) (1998) 127e136.
[133] C. Wu, Methods of improving mechanical and biomedical properties of CaeSi-based
ceramics and scaffolds, Expert Rev. Med. Dev. 6 (3) (2009) 237e241.
[134] G.A. Fielding, A. Bandyopadhyay, S. Bose, Effects of silica and zinc oxide doping on
mechanical and biological properties of 3D printed tricalcium phosphate tissue engineering
scaffolds, Dent. Mater. 28 (2) (2012) 113e122.
[135] L.-C. Gerhardt, A.R. Boccaccini, Bioactive glass and glass-ceramic scaffolds for bone
tissue engineering, Materials 3 (7) (2010) 3867e3910.
[136] J. Wang, L.L. Shaw, Nanocrystalline hydroxyapatite with simultaneous enhancements in
hardness and toughness, Biomaterials 30 (34) (2009) 6565e6572.
[137] G. Chiara, et al., Nanostructured biomaterials for tissue engineered bone tissue recon-
struction, Int. J. Mol. Sci. 13 (1) (2012) 737e757.
[138] Z. Ge, Z. Jin, T. Cao, Manufacture of degradable polymeric scaffolds for bone regenera-
tion, Biomed. Mater. 3 (2) (2008) 022001.
[139] B. Zavan, et al., Hyaluronan based porous nano-particles enriched with growth factors for
the treatment of ulcers: a placebo-controlled study, J. Mater. Sci. Mater. Med. 20 (1) (2009)
235e247.
[140] K.S. Vasanthan, et al., Role of biomaterials, therapeutic molecules and cells for hepatic
tissue engineering, Biotechnol. Adv. 30 (3) (2012) 742e752.
[141] C. Shuai, et al., Structure and properties of nano-hydroxypatite scaffolds for bone tissue
engineering with a selective laser sintering system, Nanotechnology 22 (28) (2011)
285703.
[142] A. Salinas, M. Valletregi, Bioactive ceramics: from bone grafts to tissue engineering, RSC
Adv. 3 (28) (2013) 11116e11131.
[143] X. Liu, et al., Bioactive calcium silicate ceramics and coatings, Biomed. Pharmacother. 62
(8) (2008) 526e529.
[144] A.M. Barradas, et al., Osteoinductive biomaterials: current knowledge of properties,
experimental models and biological mechanisms, Eur. Cells Mater. 21 (12) (2011)
4532e4545.
[145] X. Li, et al., Influences of the steam sterilization on the properties of calcium phosphate
porous bioceramics, J. Mater. Sci. Mater. Med. 27 (1) (2016) 1e10.
[146] L.L. Hench, Bioceramics: from concept to clinic, J. Am. Ceram. Soc. 74 (7) (2010)
1487e1510.
[147] I. Rehman, et al., Analysis of surface layers on bioactive glasses, Biomaterials 15 (10)
(1994) 865e870.
[148] K.M. Nuss, B. von Rechenberg, Biocompatibility issues with modern implants in bone-a
review for clinical orthopedics, Open Orthop. J. 2 (2008) 66.
[149] S.-Y. Park, et al., Extracellular low pH modulates phosphatidylserine-dependent phago-
cytosis in macrophages by increasing stabilin-1 expression, J. Biol. Chem. 287 (14) (2012)
11261e11271.
[150] H. Fan, et al., Surface structural biomimetics and the osteoinduction of calcium phosphate
biomaterials, J. Nanosci. Nanotechnol. 7 (3) (2007) 808e813.
[151] A. Clark, L. Hench, H. Paschall, The influence of surface chemistry on implant interface
histology: a theoretical basis for implant materials selection, J. Biomed. Mater. Res. 10 (2)
(1976) 161e174.
[152] L.L. Hench, J.M. Polak, Third-generation biomedical materials, Science 295 (5557) (2002)
1014e1017.
[153] X. Lu, Y. Leng, Theoretical analysis of calcium phosphate precipitation in simulated body
fluid, Biomaterials 26 (10) (2005) 1097e1108.
[154] H.S. Fan, et al., Surface characteristics and osteoinductivity of biphasic calcium phosphate
ceramics with different sintering temperature, in: Key Engineering Materials, Trans Tech
Publ, 2006.
[155] H. Fan, et al., Surface structural biomimetics and the osteoinduction of calcium phosphate
biomaterials, J. Nanosci. Nanotechnol. 7 (3) (2007) 808e813.
[156] H.S. Fan, et al., Surface characteristics and osteoinductivity of biphasic calcium phosphate
ceramics with different sintering temperature, Key Eng. Mater. 309e311 (2006)
1299e1302.
[157] Y. Bo, et al., Processing and properties of bioactive surface-porous PEKK, Acs Bio-
materialsence & Engineering 2 (6) (2016) p. acsbiomaterials.6b00103.
[158] B. Yuan, et al., Comparison of osteointegration property between PEKK and PEEK: effects
of surface structure and chemistry, Biomaterials 170 (2018) 116.
[159] Y. Tan, et al., Expression of core binding factor 1 and osteoblastic markers in C2C12 cells
induced by calcium phosphate ceramics in vitro, J. Biomed. Mater. Res. A 82 (1) (2007)
152e159.
[160] M. Sarikaya, Biomimetics: materials fabrication through biology, Proc. Natl. Acad. Sci. 96
(25) (1999) 14183e14185.
[161] J.D. Hartgerink, E. Beniash, S.I. Stupp, Self-assembly and mineralization of peptide-
amphiphile nanofibers, Science 294 (5547) (2001) 1684e1688.
[162] N.C. Seeman, A.M. Belcher, Emulating biology: building nanostructures from the bottom
up, Proc. Natl. Acad. Sci. 99 (Suppl. 2) (2002) 6451e6455.
[163] H. Cölfen, S. Mann, Higher-order organization by mesoscale self-assembly and trans-
formation of hybrid nanostructures, Angew. Chem. Int. Ed. 42 (21) (2003) 2350e2365.
[164] A.-W. Xu, Y. Ma, H. Cölfen, Biomimetic mineralization, J. Mater. Chem. 17 (5) (2007)
415e449.
[165] F.A. Müller, et al., Whisker-reinforced calcium phosphate cements, J. Am. Ceram. Soc. 90
(11) (2010) 3694e3697.
[166] W. Suchanek, et al., Processing and mechanical properties of hydroxyapatite reinforced
with hydroxyapatite whiskers, Biomaterials 17 (17) (1996) 1715e1723.
[167] X. Ye, et al., Fabrication and characterization of porous 3D whisker-covered calcium
phosphate scaffolds, Mater. Lett. 128 (2014) 179e182.
[168] Y. Zhu, et al., Bone regeneration with micro/nano hybrid-structured biphasic calcium
phosphate bioceramics at segmental bone defect and the induced immunoregulation of
MSCs, Biomaterials 147 (2017) 133.
[169] P.J. Marie, et al., Mechanisms of action and therapeutic potential of strontium in bone,
Calcif. Tissue Int. 69 (3) (2001) 121e129.
[170] M. Yamaguchi, Role of zinc in bone formation and bone resorption, J. Trace Elem. Exp.
Med. 11 (2-3) (2015) 119e135.
[171] A.M. Cortizo, et al., Osteogenic activity of vanadyl(IV)-ascorbate complex: evaluation of
its mechanism of action, Int. J. Biochem. Cell Biol. 38 (7) (2006) 1171e1180.
[172] E. Hinoi, T. Takarada, Y. Yoneda, Glutamate signaling system in bone, J. Pharmacol. Sci.
94 (3) (2004) 215e220.
[173] P.J. Marie, The calcium-sensing receptor in bone cells: a potential therapeutic target in
osteoporosis, Bone 46 (3) (2010) 571e576.
Another random document with
no related content on Scribd:
been no paralysis, and the hemorrhages were probably not the
immediate cause of death.
Durand-Fardel gives a table of supposed causes in 21 cases of

persons over fifty: 8 of these were connected with either habitual use
of liquor or a debauch; 9 had an attack immediately after a meal.
After naming all these causes, it must be said that in many cases it is
impossible to find any reason for the occurrence of the hemorrhage
at the particular moment it comes. A person may go to bed in
apparent health, and be found some hours afterward unconscious
and comatose, or unable to stir hand or foot on one side, or to
speak. Gendrin, as quoted by Aitken, states that of 176 cases, 97
were attacked during sleep. The attack may come on when the
patient is making no special muscular effort and under no special
excitement. It is simply the gradual progress of the lesion, which has
reached its limit.
SYMPTOMATOLOGY.—If we take as a point of departure the fully-

developed attack, such as most frequently is found with a large and
rapid hemorrhage into the cerebral hemispheres, pons, or
cerebellum, the symptoms are those usually spoken of as an
apoplectic attack, shock, or stroke, or, as the Germans say,
Hemorrhagische Insult. Trousseau quotes as a satisfactory definition
the words of Boerhaave: “Apoplexia dicitur adesse, quando repente
actio quinque sensuum externorum, tum internorum, omnesque
motus voluntarii abolentur, superstite pulsu plerumque forti, et
respiratione difficili, magna, stertente, una cum imagine profundi
perpetuique somni.”
Loss of consciousness, abolition of voluntary motion and sensation,

and usually stertor, the appearance of the patient being that of one in
deep sleep, are found in the extreme cases. In others the loss of
consciousness and sensation are not complete; the patient can be
aroused enough to utter a grunt or raise a hand to his face in order
to brush away a fly or the hand of the physician who is trying to raise
his eyelids, or can make a grimace to show that he is hurt, the face
returning to its indifferent expression as soon as the cause of
irritation is removed. Although the grade of action, both sensitive and
motor, seems to be a little above the purely reflex, it is but very
slightly so, and probably is not sufficient to remain an instant in the
memory.
The rapidity with which this condition comes on varies widely, from a
very few minutes, or even seconds, to some hours. It may even
diminish for a time and return. The cases in which unconsciousness
is most rapidly produced are apt to be meningeal and ventricular,
and presumably depend upon the rupture of vessels of considerable
size, although the location among the deeper ganglia, where the
conductors of a large number of nervous impulses are gathered into
a small space, will, of course, make the presence of a smaller clot
more widely felt. Even in these, however, the onset is not absolutely
instantaneous, and the very sudden attack is rather among the
exceptions. Trousseau denies having seen, during fifteen years of
hospital and consulting practice, a single case in which a patient was
suddenly attacked as if knocked down with a hammer, and that since
he had been giving lectures at the Hotel Dieu he had seen but two
men and one woman in whom cerebral hemorrhage presented itself
from the beginning with apoplectiform phenomena. In each of these
the hemorrhage had taken place largely into the ventricles.
Lidell gives the following case: A colored woman, aged forty-nine,

was engaged in rinsing clothes, and while in a stooping posture
suddenly fell down upon her left side as if she had been struck down
by a powerful blow. She was picked up insensible, and died in ten or
fifteen minutes. The hemorrhage was chiefly meningeal, and
especially abundant about her pons and medulla oblongata. The
fourth ventricle was full of blood, and there were clots in the lateral
ventricles.
A woman, aged about forty, had been hanging out clothes in an

August sun. She was observed to run out of the house screaming,
and fell to the ground unconscious. This was at 1 P.M., and she died
at 3.30 P.M. Her temperature just after death was 107.2°. The
neighborhood of the posterior surface of the pons Varolii was
occupied by a broken-down-looking mass, appearing like an
aggregation of small apoplexies (hemorrhages), involving and
breaking down the middle crura of the cerebellum. There was no
fatty degeneration nor any miliary aneurism. (I do not know upon
how thorough an examination this last statement rests.)
In a large number of cases it is difficult to say, in the absence of any

observation, intelligent or otherwise, exactly how rapid the onset of
the symptoms may have been, but in those which occur where the
patient is watched or is in the company of observant persons it is
almost invariable to meet with symptoms less than unconsciousness
which denote the actual beginning of the hemorrhage. From the
nature of the lesion it can rarely give rise to symptoms which justify
the epithet of fulminating in the sense of struck with a thunderbolt.
The unconsciousness, so far as can be known, does not depend on
the injury of any one special small point of the brain in which
consciousness resides, but upon the compression of a considerable
portion, which must necessarily take place gradually, but with a
rapidity proportioned to the size of the current which issues from the
ruptured vessel and the ease with which pressure can diffuse itself
over a large area. It is undoubtedly the greater facility offered to such
diffusion by the communication of the hemorrhage with the so-called
cavity of the arachnoid and the ventricles which gives to these forms
a peculiar severity. The difference between a hemorrhage spreading
through all the ventricles or over a large surface of the brain, and
one which is limited to a focus in the substance of one hemisphere,
being restrained by more or less firm tissue, may be illustrated by the
gain in power in the hydraulic press from the transfer of the stream of
water from a small cylinder to a larger one.
Vomiting is a symptom of some importance in diagnosis, being not

very common in cerebral hemorrhage, but very frequent in
cerebellar.
Whether of sudden, rapid, or slow development, the apoplectic

attack is, in its main features, described in the aphorism of
Boerhaave given above. The muscular relaxation of the face imparts
to it an expressionless, mask-like character; the limbs lie motionless
by the side, unless they can be excited to some slight movement by
some painful irritation or are agitated by convulsions, or in a
condition of rigid spasm; the face may be pale or flushed; the cheeks
flap nervelessly—le malade fume la pipe.
Swallowing, in the deepest coma, is not attempted. The fluid poured

into the mouth remains, and distributes itself according to the laws of
gravity without exciting reflex movements of the pharynx. When the
depression is less profound, it may excite coughing or be swallowed.
An attempt to swallow when the spoon touches the lips indicates a
considerably higher degree of nervous activity. Respiration may be
slow, but when the case is to terminate fatally rises with the pulse
and temperature. It is often stertorous and difficult, the obstruction
consisting partly in the gravitation backward of the soft palate and
tongue, and partly in the accumulation of fluids in the pharynx.
Hence stertor is in some cases only an accidental phenomenon,
depending upon the position of the patient on the back, and can be
relieved by turning him on his side and wiping out the mouth as far
back as can be reached. Cheyne-Stokes respiration occurs in severe
cases, though not confined to necessarily fatal ones.
The general temperature in cerebral hemorrhage has been studied

enough to make it of considerable value, especially in prognosis. In a
case which extends over a sufficiently long time several stages can
be distinguished which in shorter ones may be wanting. An initial
period of depression is described by Bourneville17 as occurring
immediately after an attack, in which the temperature falls a degree
or two below the normal, and, according to his view, continues
depressed if death takes place rapidly. He gives the case of a man
who died very shortly after an attack (his second one), where the
temperature, taken in the rectum at the moment of death, was 35.8°.
In cases which survive longer this initial fall passes either into a
stage where it oscillates within the neighborhood of the normal or
immediately begins to rise; the latter occurrence indicates an
impending fatal termination (unless, of course, something else can
be found to account for it). In the former condition we find patients
whose life may be indefinitely prolonged for days or weeks, when, if
a fatal termination is to result, the thermometer again indicates a
rise.
17 Études cliniques et thermométriques sur les Maladies du Système nerveux, 1872.
The initial fall of temperature is not so likely to be observed except in

institutions like the Salpêtrière, where large numbers of old persons
are collected and under close medical surveillance; and, indeed, it
may be doubted, even from Bourneville's own table, whether the rule
is one without exceptions. At any rate, the rise is a more important
phenomenon than the fall. When the rise of temperature is
interrupted by a fall, and then continues again, it is due, according to
the author already quoted, to a renewal of the hemorrhage.
These changes of temperature may be noted with various locations

of the lesion, but it seems probable that further study might make
them useful in diagnosis as well as prognosis. Hale White reports the
case of a boy aged six and a half years, who was found unconscious
with right hemiplegia, and who afterward had many and various
paralyses with hyperpyrexia, the highest temperature being 107°. He
lived long enough for secondary degeneration to extend down the
crura and into the anterior cornua. A small soft patch a quarter of an
inch in diameter existed at the anterior part of each corpus
striatum.18
18 Guy's Hosp. Rep., 1882.
FIG. 37.
The chart W. H. (Fig. 37) is from a man aged fifty who fell in the
street while returning from work at noon, and whose axillary
temperature was taken at 5 P.M. and every two hours thereafter until
death. The hemiplegia was not very marked, but the hemorrhage
was extensive, involving the pons and left crus cerebri, the external
capsule, left crus cerebelli, and medulla, bursting through into the
fourth ventricle.
FIG. 38.
The chart M. M. (Fig. 38), as taken from Bourneville, represents the
course of the temperature in a rapid case: each perpendicular line
denotes an hour.
The difference in the temperature of the two sides has been

variously stated, and probably depends on a number of factors
besides the length of time that has elapsed since the first attack.
There is probably, however, a tendency to excess of heat on the
paralyzed side soon after the attack, owing to vaso-motor paralysis;
and this difference will be more marked in the hands than in the
axillæ. After a length of time which may be from days to months the
temperature becomes equalized, or more frequently the relation is
reversed, the paralyzed side being colder as atrophy takes place.
Lepine19 gives a case where the axillary temperatures of the two
sides continued the same within a small fraction of a degree for three
days, and then separated very slowly, until at death the paralyzed
side was six-tenths of a degree (Cent.) hotter than the other, in both
being inferior to the rectal (107° Cent.).20
19 Mémoires de Société de Biol., 1867.
20 The chart in the original, and as reproduced by Bourneville, is wrongly lettered. The
text says that the left side was the hotter.
FIG. 39.
The chart C. M. (Fig. 39) shows the excess of temperature in a case

of meningeal hemorrhage. The dotted line is from the paralyzed side.
The first observation was made two and a half hours after the attack.
A very interesting case is reported by Johnson21 of crossed
hemiplegia, where the temperature was about a degree higher on
the paralyzed side of the body, and, corresponding to this, the
sphygmograph showed a great diminution of tension; the lesion is
supposed to have been a hemorrhage in the pons. Johnson, in
commenting on the statement of Lorain that in all cases of
hemiplegia the pulse is more full on the paralyzed side, says that it is
incorrect for ordinary cases of hemorrhage into the corpus striatum,
though true in his own case.
21 Brit. Med. Journ., Jan. 6, 1877.
The most marked differences of temperature have been observed

where the lesion has been in the neighborhood of the pons, crus
cerebri, or medulla oblongata. In a case reported by Allbutt there
was a difference of 1.6°; the radial pulse was softer and fuller on the
paralyzed side, and the cheek upon that side was flushed.22 The
pulmonary hemorrhages which have been noticed by Brown-
Séquard and others in animals after cerebral lesions, and the
extravasation, congestion, subpleural ecchymoses noted by Ollivier23
in cerebral apoplexy, are probably to be referred to vaso-motor
disturbances.
22 Med. Times and Gaz., Dec. 4, 1869.
23 Archives générales, 1873, 167.
Much more attention has been paid to the pulse than to the
temperature, but it is less easy to lay down definite rules in regard to
it. It may vary in either direction. When the case is approaching a
fatal termination the pulse is apt to accompany the temperature in a
general way in its rise, though not necessarily following exactly, as is
seen in the chart in Fig. 38.
The throbbing or bounding of the arteries often described may

indicate increased activity of heart, but means at the same time
vaso-motor relaxation. The urine and feces are often passed
involuntarily.
In some rare cases symptoms closely resembling those produced in
animals by section of the sympathetic have been seen. These are
false ptosis, narrowing of the palpebral opening and sinking of the
globe of the eye into the orbit, diminution in the size of the pupil,
higher temperature on the paralyzed side of the face and the
corresponding ear, abnormal secretion of the eye, nose, and mouth
on the same side.24 They are supposed to indicate a paralysis of the
sympathetic.
24 Nothnagel, quoted by Grasset.
The condition of general relaxation may be so profound as to cover

up everything else, but in many cases true paralytic symptoms may
be discovered or provoked, which even at an early period give us
information as to the locality and nature of the lesion.
A greater degree of muscular relaxation may be manifest on one

side of the face than the other; the forehead may be a little smoother
on one side, the corner of the mouth drooping, the downward line
from the ala of the nose flattened, and the cheek flapping. There
may be a little greater resistance to passive motion of the limbs on
one side; one hand on being raised may drop helplessly back to the
bed, while the other is laid slowly down; the right hand when pinched
lies motionless and without power to escape the pain until the left
comes to its assistance. Irregularity of the pupils, if present, is an
important sign, but its absence signifies nothing.
One of the most significant signs is the conjugate deviation of the

eyes, both eyes and the head being turned strongly to one side or
the other. When the lesion is above the pons and is irritative, as in
the early stage of hemorrhage, the deviation is toward the side of the
body affected and away from the lesion; when paralysis is
established, away from the paralysis and toward the lesion. Below
the pons the rule is reversed. The spastic stage of conjugate
deviation may coincide with stiffness (early rigidity) of the paralyzed
limbs. This deviation must not be mistaken for an accidental position
of the head. The patient should be addressed from the side away
from which he is looking. Sometimes the eyes can be brought to the
median line, and not beyond. An attempt to turn the head forcibly
beyond the median line occasionally causes pain. The value of this
symptom in diagnosis has been denied, but a part at least of the
apparent contradictions have arisen from the neglect to notice
whether it were of a paralytic or spastic character.
As the condition of unconsciousness gradually passes off, the face

regaining, at least in part, its natural and more intelligent expression,
the eyes trying to follow the movements of surrounding persons, an
attempt being made, perhaps only by an unintelligible sound or by a
nod, to answer questions, the tongue being protruded, or at least an
attempt toward it made, and some motions being made with the
limbs,—the exact extent and intensity of the paralysis become more
apparent. Conjugate deviation, if it have existed, may disappear
before the other symptoms, or, if it has been of the rigid form
depending on an irritative lesion, it may become paralytic, and is
then in the opposite direction. The patient is then usually found to be
in a condition of hemiplegia, and at this point the history of
hemorrhagic apoplexy becomes identical with that of paralysis from
hemorrhage where no truly apoplectic condition has been present.
Lidell states that in more than one-third of all cases of cerebral

hemorrhage hemiplegia is developed without loss of consciousness
or coma. In some, the paralysis precedes unconsciousness, which
then slowly supervenes.
Hemiplegia (ἥμι, half, πληγη blow) is a paralysis or paresis of a part

of the voluntary muscles of one side of the body, and a few, in some
cases, on the other, and is undoubtedly to be referred to a lesion
interrupting the nervous communication between the cortical centres
of motion and the nuclei of the motor nerves, cerebral and spinal; the
conductors passing through the corpora striata, the internal capsule,
the peduncles, and crossing in great part to the other side above or
at the lower border of the medulla oblongata, and passing down the
crossed pyramidal tracts of the cord, to be finally connected with the
anterior gray columns of the cord. The portion which does not
decussate passes down the inner border of the anterior columns
under the name of columns of Türck. The amount of decussation
which takes place varies somewhat, and the suggestion has been
made, in order to explain certain cases of paralysis occurring on the
same side with the lesion, that possibly in some rare cases there
may be no decussation. It has never been shown, however, that this
condition, highly exceptional if even it ever occurs, is present in such
cases.
It may be said in a general way, although exceptions to the rule can

be found, that it is those muscles trained to separate, specialized, or
non-associated movements which are chiefly affected, while those
which are habitually associated in function with those of the other
side are less or not at all so. It would not, however, be in the least
correct to say that specialized or educated movements of any set of
muscles are alone paralyzed, since the fingers, which are trained to
the most independent movements, are often just as incapable of
making the slightest movement of simple flexion as of writing or
sewing.
We have in ordinary hemiplegia more or less paralysis of the upper

facial, the patient not being able to close his eye or to wink quite so
well as on the paralyzed side. The forehead may be smoother on the
paralyzed side. This condition is usually slight and of short duration,
but varies in different cases. Paralysis of the lower facial angle of the
mouth and cheek is usually better marked, but not absolute. The
corner of the mouth droops, perhaps permits the saliva to escape;
the naso-labial fold is less deep, and the glabella deviated away from
the paralyzed side. The cheek flaps with respiration. The difference
between this facial paralysis connected with hemiplegia and that
dependent upon a lesion of the trunk or distribution of the nerve
(Bell's), as in caries of the temporal bone or the so-called rheumatic
paralysis, is very striking, the latter being so much more complete,
and, by affecting the orbicularis palpebrarum so as to prevent
closure of the eye, giving a very peculiar expression to the
countenance. This distinction between the two portions of the facial
seems to make an exception to the rule stated above, since in most
persons the movements of the corner of the mouth and of the cheek
are quite as closely bilaterally associated as those of the eyelids.
Paralyses of the third, fourth, and sixth pairs upon one side of the
body are comparatively rare in hemiplegia, and when present are
usually referable to localized lesions in the pons. They are to be
looked upon as something superadded to the ordinary hemiplegia.
These nerves, however, are affected in the peculiar way already
spoken of as conjugate deviation, which phenomenon would seem to
denote that muscles accomplishing combined movements in either
lateral direction of both eyes, rather than all the muscles of each, are
innervated from opposite sides—i.e. that the right rectus externus
and the left rectus internus are innervated from the left motor
centres, and vice versâ. Exactly the same remark will apply to the
muscles of the neck which cause the rotation of the head seen
together with the deviation of the eyes. The muscles controlling
deviation to one side, although situated upon both sides of the
median line, are apparently innervated from the side of the brain
toward which the head is turned in paralysis.
The tongue is usually protruded with its point toward the paralyzed
side; and this is simply for the reason that it is pushed out instead of
pulled, and the stronger muscle thrusts the tongue away from it. The
motor portion of the fifth is, according to Broadbent, affected to a
certain extent, the bite upon the paralyzed side being less strong.
The hand and the foot are the parts most frequently and most
completely affected, but one or the other may be partially or wholly
spared, though the latter is rare. The muscles of the limbs nearer the
trunk may be less affected, so that the patient may make shoulder or
pelvis movements when asked to move hand or foot. In severe
cases even the scapular movements may be paralyzed. The
muscles of the trunk are but slightly affected, though Broadbent
states that a difference in the abdominal muscles on the two sides
may be perceived as the patient rises from a chair. The respiratory
movements are alike on the two sides. A woman in the hospital
service of the writer had a quite complete left hemiplegia at about the
seventh month of pregnancy. There was some return of motion at
the time of her confinement. None of the attendants could perceive
any difference in the action of the abdominal muscles of the two
sides, although, of course, the usual bracing of the hand and foot
upon the left side was wanting. The pains were, however, generally
inefficient, and she was delivered by turning. Muscular weakness
often exists, and in some cases the non-paralyzed side shows a
diminution of power.
The sphincters of the bladder and rectum frequently, and in severe

cases almost invariably, lose their activity for a time. It is possible,
however, that in some cases of alleged inability to retain urine and
feces the defect is really mental, and akin to the dirty habits of the
demented. The involuntary muscles probably take no part in
hemiplegia, with the very important exception of the muscular coats
of the arteries, which apparently share to a certain extent, and
sometimes the iris.
Speech may be attempted, and the words be correct, so far as they

can be understood, though the patient is apt to confine his remarks
to the shortest possible answering of questions. It is, however, thick
and indistinct, since the muscles of the tongue and lips are but
imperfectly under the control of the will. This condition may be
connected with paralysis of either side, and is to be sharply
distinguished from aphasia or mental inability to select the proper
word or to determine the necessary movements for its pronunciation.
Aphasia is almost invariably connected with paralysis of the right
side, and will be minutely spoken of hereafter. There is, of course,
nothing to prevent the coexistence of the two conditions, but aphasia
cannot well be shown to exist until we have reason to suppose, first,
that the patient has ideas to express, and secondly, that the
paralysis of the muscles of the lips and tongue has more or less
completely disappeared. The patient may indistinctly mumble a word
which, however, can be understood to be appropriate to the occasion
(defective articulation, glosso-labial paralysis), or, on the other hand,
pronounce with distinctness an entire wrong word or a number of
sounds without meaning (aphasia).
Sensibility—that is, ordinary cutaneous sensation—and, so far as we
can judge, the special senses, are not greatly affected after the deep
coma has passed off, but exceptions to this rule will be noted later.
Having described this most typical but not most common form of
cerebral hemorrhage—that is, the form in which both lesion and
symptoms are most distinct and can be most clearly connected—we
have a point of departure for conditions less clearly marked and less
easily explained.
It is probable that cerebral hemorrhage is much less likely than

cerebral embolism to take place without any disturbance of
consciousness or abnormal sensations; but there can also be little
doubt that a certain amount of paralysis is often accompanied by no
other symptoms, and post-mortem appearances often show the
remains of small hemorrhages which have passed unnoticed or are
lightly estimated. It is highly probable that small hemorrhages may
give rise to symptoms which pass for only a little accidental vertigo
or a slight feeling of faintness, until a later and more serious attack
gives a more definite explanation.
On the other hand, we have a set of cases in which all the symptoms
of cerebral hemorrhage may be present without the lesion. Many of
these are of course due to embolism, which will be considered later;
but besides this condition, recognized as softening for many years,
we find described under the head of simple, congestive, serous, and
nervous apoplexy cases where sudden or rapid loss of
consciousness occurs with general muscular relaxation, which, when
fatal, show nothing beyond changes in the circulation—i.e. in the
amount of blood in the cerebral vessels or of serum in the meshes of
the pia or at the base of the brain.
Besides these, there are cases of temporary unconsciousness with

complete recovery—the coup de sang of the French, or rush of blood
to the head, which are attributed to congestion of the brain—a theory
difficult to prove or disprove, but not in itself unreasonable.
Trousseau, without denying the possibility, or even probability, of
such a condition, says that which has been called apoplectiform
cerebral congestion is in the greater number of cases an epileptic or
eclamptic accident, sometimes a syncope. Simple epileptic
vertigoes, vertigoes connected with a bad condition of the stomach
or diseases of the ear, are wrongly considered as congestions of the
brain. He speaks of various conditions, such as violent attacks of
whooping cough, the expulsive efforts of women in labor, the
congested faces of laborers under heavy burdens, to show that
cerebral congestion does not give rise to an apoplectiform attack;
and it is undoubtedly true that, as a rule, no long-continued attack is
the result; but it must be within the personal experience of almost
every one that decided cerebral disturbance is produced for a few
moments by such efforts, as, for instance, blowing a fire with the
head down. Besides this, a laborer under a heavy load is
presumably healthy and accustomed to his work, so that his arteries
may be supposed capable of maintaining a due balance between
arterial and venous blood in the brain; and, again, although the
ordinary efforts of women in labor do not cause unconsciousness,
puerperal convulsions, involving a longer period of violent muscular
action, may do so, and even give rise to hemiplegia.
Whatever name we may adopt for the temporary cases which

recover, there are others, and fatal ones, which are not explained by
any change in nomenclature. Epilepsy may, it is true, occur under
such circumstances that no convulsion is observed, but, on the other
hand, convulsions may accompany not only an attack of
unconsciousness, but actual cerebral hemorrhage.
Cases of sudden death with no discoverable lesion furnish abundant

opportunity and temptation for conjecture, and it is well known that
too much dependence must not be placed upon the post-mortem
appearances as to the amount of blood in the brain before death,
and probably just as little upon the amount of serum, except as
indicating a condition of atrophy.
Syncope, either from over-stimulation of the pneumogastric or from

simple failure of the heart, may be put forward to explain some cases
of sudden death, but seems to have no advantage as a universal
theory over the older one, which meets with so little favor. Lidell
gives no less than seventeen cases which he classifies as
congestive or serous apoplexy. They are not all equally conclusive,
and were almost all of alcoholics. In some of these there were
absolutely no appearances which could account for death. The two
most characteristic of congestive apoplexy were, first, a young
negress who experienced a violent fit of passion, became
unconscious, with stertorous breathing, and died, having had some
tonic spasms. The brain contained a large amount of blood in the
vessels, but no effusion. Second, a semi-intoxicated woman, aged
thirty, became very angry, fell insensible, and expired almost
immediately. The brain contained an excess of blood, with no
effusion. In both these cases the patients were subject to fits under
the influence of strong excitement, but in both the author took pains
to inquire into and negative the probability of epilepsy of the ordinary
kind; and a change of name does not go far toward clearing up the
pathology.
Lidell's case (XXII.) was that of a man accustomed to alcohol, thin

and pale, who had an apoplectic fit with coma and hemiplegia. He
regained consciousness on the second day, and the hemiplegia
disappeared in a fortnight. This rapid and complete recovery,
exceptional to be sure, cannot be regarded as proof of the absence
of hemorrhage or embolism. In fact, the latter is highly probable. It is
possible that the clot may have been partially dislodged, so as to
allow some blood to pass by it, or that an exceptionally favorable
anastomosis allowed a better collateral circulation than usual to be
established.
The following case occurred in the service of the writer: An elderly

negress, who had extensive anasarca and signs of enfeebled action
of the heart without any valvular lesion being detected, after washing
her face was heard to groan, and found speechless and unable to
swallow, with complete right hemiplegia. There was a slight
improvement in a few hours, but she died two days later. The
autopsy disclosed some hypertrophy and dilatation of the heart
without valvular lesion. A careful search failed to discover any
change in the brain or obstruction in its vessels, although there was
chronic endarteritis.
The relations between epilepsy, apoplexy, and syncope are

interesting and important, but are certainly far from clear. Little is
gained by shifting obscure cases from one category to the other. If
sudden deaths be synonymous with apoplexy, we shall certainly
have to admit that apoplexy does not always demand for its cause
cerebral changes sufficiently marked to be recognizable after death.
If, on the other hand, we refer them to heart disease, we shall have
to admit that a heart without valvular disease or extensive changes
in its muscular substance may cease to beat under influences as yet
not well understood.
Since the paralysis arising from hemorrhage resembles so closely in

its progress that dependent upon occlusion of the cerebral vessels, a
further description will be deferred until the latter lesion has been
described; but this remark does not apply to the premonitory and
initiative symptoms, which may be of great importance, and which
are not always the same with the two or three sets of lesions. There
are many of them, but, unfortunately, no one among them taken
alone can be considered of high significance, unless we except what
are sometimes called premonitory attacks, which are in all probability
frequently genuine hemorrhages of so slight extent that they produce
no unconsciousness, and but slight paralysis easily overlooked. A
little indistinctness of speech or a forgetfulness of words, a droop of
one angle of the mouth, or heaviness in the movement of a foot or
hand, lasting but a few moments, may be real but slight attacks,
which may be followed either by a much more severe one, by others
of the same kind, or by nothing at all for a long time. They are
sufficient to awaken apprehension, and to show in what direction
danger lies, but they give little information as to the time of any future
attack.
Retinal hemorrhage is admitted by all modern authors to be

connected with disease of the vascular system, and hence also with
renal inflammation and cerebral lesions. The writer is greatly
indebted to Hasket Derby for the following facts: Out of 21 patients
who had retinal hemorrhage, and of whose subsequent career he
had information, 9 had some sort of apoplectic or paralytic attack; 1
had had such an attack before she was examined; 3 died of heart
disease, 1 suddenly, the cause being variously assigned to heart
disease or apoplexy; and 6 were alive when heard from, one of
these, a man of forty-eight, being alive and well fourteen years after.
Bull25 describes four cases of his own where retinal hemorrhage was
followed by cerebral hemorrhage, demonstrated or supposed in
three, while in the fourth other symptoms rendered a similar
termination by no means improbable. He quotes others of a similar
character. The total number of cases which were kept under
observation for some years is, unfortunately, not given. In a case
under the observation of the writer a female patient, aged fifty-seven,
who had irregularity of the pulse with some cardiac hypertrophy, was
found to have a retinal hemorrhage two and a half years before an
attack of hemiplegia. The hemorrhage was not accompanied by the
white spots which often accompany retinitis albuminuria.
25 Am. Journ. Med. Sci., July, 1879.
In a case reported by Amidon26 retinal and cerebral hemorrhages

seem to have been nearly simultaneous a few hours before death.
There was diffuse neuro-retinitis and old hemorrhages besides the
recent one.
26 N. Y. Med. Rec., 1878, xiv. 13.
The highly interesting observation has been made by Lionville27 that

when miliary aneurisms are present in the brain, they may often be
found in the retina also. In one case where they were very numerous
in the cerebrum, cerebellum, pons, and meninges, aneurismal
dilatations were found also in the pericardium, mesentery, cervical
region, and carotids (the latter not being more minutely described).
There was very general atheroma and numerous points of arteritis.
The retinal aneurisms varied in size from those requiring a power of
ten or twenty diameters to be examined up to the size of a pin's head
or a millet-seed. He thinks they might have been recognized by the
ophthalmoscope.
27 Comptes Rendus de l'Acad. des Sci., 1870.
The hemorrhages accompanying idiopathic anæmia and other

diseases with a similar tendency are not to be taken into this
account. Hemorrhage accompanying optic neuritis is likely to be due
to some disease of the brain other than the one under consideration.
Mental disturbances of various kinds have been considered as

significant, and Forbes Winslow gives a great many instances of
different forms, but they are to be looked upon rather as indicating
chronic cerebral changes which may result in various conditions, of
which hemorrhage may be one, than as furnishing any definite
indication of what is to be expected. Loss of memory should be
regarded in this way. Some acute or temporary conditions of
depression may affect the nutrition of the brain in such a way, without
having anything to do with hemorrhage actual or anticipated.
Aberrations of the special senses are often observed, such as noises

in the ears more or less definite, the sight of colors (red), or being
unable to see more than a portion of an object. The fact to which
these testify is probably a localized disturbance of the circulation
which may not precede rupture of the vessels.
Distinct hallucinations of hearing, followed by those of smell and

succeeding irritability, sleeplessness, were observed by Savage28 in
a case which terminated soon after in apoplexy.
28 Journ. Ment. Sci., 1883, xxix. 90.
There are few symptoms which are more likely to excite alarm and
apprehension of a stroke of paralysis than vertigo or attacks of
dizziness, but it is too common under a great variety of
circumstances to have much value, and is, as a matter of fact, rarely
a distant precursor of intracranial hemorrhage, although it frequently
appears among the almost initiatory symptoms, especially when the

PDF Bioactive Materials For Bone Regeneration 1St Edition Jiang Chang Ebook Full Chapter

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

PDF Bioactive Materials For Bone Regeneration 1St Edition Jiang Chang Ebook Full Chapter

Uploaded by

Copyright:

Available Formats

Bioactive Materials for Bone

Regeneration 1st Edition Jiang Chang

Development of China s Cultural Industry Chang Jiang

Mesoporous materials for advanced energy storage and

Mesoporous Materials for Advanced Energy Storage and

Mesoporous Materials for Advanced Energy Storage and

Bone Response to Dental Implant Materials 1st Edition

Tissue Engineering Strategies for Organ Regeneration

Bioactive Natural Products for Pharmaceutical

Housing Regeneration: A Plan for Implementation Charles

Library of Congress Cataloging-in-Publication Data

British Library Cataloguing-in-Publication Data

For information on all Academic Press publications visit our

Publisher: Matthew Deans

Typeset by TNQ Technologies

Bioactive Materials for Bone Regeneration. https://doi.org/10.1016/B978-0-12-813503-7.00001-7

1.2.1.2.1 Hydrother- 1.3.2.2 Interactions between

1.4.3.1 Autocrine effect of 1.4.3.2 Paracrine effect from

Bioactive materials play an increasingly important role in regenerative

Fabrication methods of bioactive

1.1.1 Material characteristics of bioactive materials for

1.1.1.2 Porous structure

1.1.1.3 Surface micro- and nanostructure

1.1.2 Design of porous bioactive materials

1.1.2.2 Molding of porous structure

TABLE 1.1 Fabrication methods for three-dimensional porous ceramic

process is low-cost, quick, and easy, whereas its shortcoming is difficulty in

In recent years, 3D printing methods have been widely developed and

1.1.2.3 Sintering technologies

Each sintering process has varied advantages, disadvantages, and application

TABLE 1.2 Advantages and disadvantages of different ceramic sintering

Methods Advantages Disadvantages

1.1.2.4 Surface modification methods

1.1.3 Main challenges and prospects

satisfying and need further optimization to endow them with tissue-

In fact, current biomaterials still have relatively low bioactivity compared

1.1.3.2 Enhancing bioactivity and mechanical property methods

1.1.3.2.2 Nanoscale topography

fabricated by modified microwave sintering [4,39]. The obtained nano-

1.1.3.2.3 Whisker reinforcement

1.1.3.2.4 Trace ion doping

[24] P. Habibovic, et al., Osteoconduction and osteoinduction of low-temperature 3D printed

[68] J. Liu, et al., Rapid formation of hydroxyapatite nanostructures by microwave irradiation,

Durand-Fardel gives a table of supposed causes in 21 cases of

SYMPTOMATOLOGY.—If we take as a point of departure the fully-

Loss of consciousness, abolition of voluntary motion and sensation,

Lidell gives the following case: A colored woman, aged forty-nine,

A woman, aged about forty, had been hanging out clothes in an

In a large number of cases it is difficult to say, in the absence of any

Vomiting is a symptom of some importance in diagnosis, being not

Whether of sudden, rapid, or slow development, the apoplectic

Swallowing, in the deepest coma, is not attempted. The fluid poured

The general temperature in cerebral hemorrhage has been studied

The initial fall of temperature is not so likely to be observed except in

These changes of temperature may be noted with various locations

The difference in the temperature of the two sides has been

The chart C. M. (Fig. 39) shows the excess of temperature in a case

The most marked differences of temperature have been observed

23 Archives générales, 1873, 167.

The throbbing or bounding of the arteries often described may

The condition of general relaxation may be so profound as to cover

A greater degree of muscular relaxation may be manifest on one

One of the most significant signs is the conjugate deviation of the