Innovative High-Pressure Fabrication Processes For Porous Biomaterials-A Review

Innovative high-pressure fabrication processes for porous
biomaterials-A review
Mythili Prakasam, Jean-François Silvain, Alain Largeteau
To cite this version:

Mythili Prakasam, Jean-François Silvain, Alain Largeteau. Innovative high-pressure fabrication pro-
cesses for porous biomaterials-A review. Bioengineering, MDPI, 2021, 8 (11), 170 (22 p.). �10.3390/bio-
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Review
Innovative High-Pressure Fabrication Processes for Porous

Biomaterials—A Review
Mythili Prakasam *, Jean-François Silvain and Alain Largeteau
CNRS, Univ. Bordeaux, Bordeaux INP, ICMCB, UMR 5026, F-33600 Pessac, France;
[email protected] (J.-F.S.); [email protected] (A.L.)
* Correspondence: [email protected]; Tel.: +33-5-4000-8435
Abstract: Biomaterials and their clinical application have become well known in recent years and
progress in their manufacturing processes are essential steps in their technological advancement.
Great advances have been made in the field of biomaterials, including ceramics, glasses, polymers,
composites, glass-ceramics and metal alloys. Dense and porous ceramics have been widely used for
various biomedical applications. Current applications of bioceramics include bone grafts, spinal fu-
sion, bone repairs, bone fillers, maxillofacial reconstruction, etc. One of the common impediments
in the bioceramics and metallic porous implants for biomedical applications are their lack of me-
chanical strength. High-pressure processing can be a viable solution in obtaining porous biomateri-
als. Many properties such as mechanical properties, non-toxicity, surface modification, degradation
rate, biocompatibility, corrosion rate and scaffold design are taken into consideration. The current
review focuses on different manufacturing processes used for bioceramics, polymers and metals
and their alloys in porous forms. Recent advances in the manufacturing technologies of porous ce-
ramics by freeze isostatic pressure and hydrothermal processing are discussed in detail. Pressure as
Citation: Prakasam, M.; Silvain, J.-F.; a parameter can be helpful in obtaining porous forms for biomaterials with increased mechanical
Largeteau, A. Innovative High strength.
Pressure Fabrication Processes for
Porous Biomaterials—A Review.
Keywords: bioceramics; metallic implants; biodegradable polymers; porous biomaterials; high
Bioengineering 2021, 8, 170.
pressure processing; freeze isostatic pressure
https://doi.org/10.3390/
bioengineering8110170
Academic Editor: Mark Edward

Byrne 1. Introduction
Porous materials [1–4] have special properties in comparison with their dense coun-
Received: 30 September 2021 terparts. Porous materials have potential applications as high-temperature filters, thermal
Accepted: 28 October 2021 gas separators, lightweight structural components, biomaterials and as thermal structural
Published: 1 November 2021 materials. Other applications, where porous materials with specific chemical composi-
tions and tailored microstructures are required, include electrodes and supports for bat-
Publisher’s Note: MDPI stays neu-
teries and solid oxide fuel cells, scaffolds for bone replacement and tissue engineering,
tral with regard to jurisdictional
heating elements, chemical sensors, solar radiation conversion, among others. Fabrication
claims in published maps and institu-
methodology plays a vital role in obtaining the pore structure, morphology and density
tional affiliations.
of pores in the porous body and their essential properties such as mechanical properties
are intricately dependent on each other. Various processing methods [5] are available for
fabricating the porous structures such as replication of polymer foams by ceramic dip
Copyright: © 2021 by the authors. Li-
coating, foaming of aqueous ceramic powder suspensions, pyrolysis of preceramic pre-
censee MDPI, Basel, Switzerland. cursors, partial sintering by pressure-less sintering, and sintering of ceramic powder com-
This article is an open access article pacts with pore-forming sacrificial phases. Frequently, the fabrication methodologies in-
distributed under the terms and con- volve employing high-temperature techniques. Employing high temperature can be det-
ditions of the Creative Commons At- rimental, especially in the case of biomaterials, as most of them consist of active therapeu-
tribution (CC BY) license (http://crea- tic molecules or water molecules in their structure. To increase the structural stability,
tivecommons.org/licenses/by/4.0/). temperature is used very often for the porous ceramics. Pressure is another important
Bioengineering 2021, 8, 170. https://doi.org/10.3390/bioengineering8110170 www.mdpi.com/journal/bioengineering

Bioengineering 2021, 8, 170 2 of 22
thermodynamic parameter that can help in fabricating porous biomaterials obtained at

low temperature with increased mechanical strength. The pressure parameter can be suc-
cessful in the case of decontamination of biomaterials that are thermosensitive. The ad-
vances in the processing techniques helps in obtaining the porous body with homogene-
ous pore distribution and desired pore morphology and by loading with active biomole-
cule or for drug-delivery systems. Cell proliferation in the porous materials is dependent
mainly on the composition of the material, pore size distribution and morphology and
open interconnected pores in the order of 50–150 µm. The structural stability of the porous
biomaterials is, in general, brittle, which is intricately dependent on parameters such as
porosity volume fraction, pore size and pore structure. Innovative high-pressure pro-
cesses can be a viable solution to consolidate and to increase mechanical strength. Porous
biomaterials have attracted great interest as scaffolds for tissue engineering, particularly
bioactive ceramics and glasses, as they are able to bond to the host tissues. From the me-
chanical aspect, the degree of porosity is vital than pore size and scaffolds with porosities
greater than 40% can be used as trabecular bones. For in vitro and in vivo performances,
pore size is more important and co-existence of macropores and micropores helps in good
vascularization of the porous biomaterial. Porosity is an important consideration for nu-
trient transfer, and promotes cell migration and proliferation, leading to regeneration and
integration.
Unique properties arise while employing the pressure parameter for processing as
the free volume of the system decreases with increasing pressure. Temperature effects act
with an increased kinetic energy as well as increased free volume. According to the Le
Chatelier-Braun principle [6], pressure affects primarily the volume of a system, while
temperature changes cause volume as well as energy changes. High-pressure processes
act as an important tool for improving the investigations on chemical bonding and conse-
quently leads to induced physico-chemical properties. High pressure can lead to struc-
tural transformations and help the synthesis of novel materials. In both cases, the conden-
sation effect (ΔV < 0 between precursors and the final product) is the general rule. In ad-
dition, through the improvement of the reactivity, high pressures can lead to materials
that are not reachable through other chemical routes. Very well-known high-pressure pro-
cessing is high-pressure torsion (HPT) which refers to the processing of metals whereby
samples are subjected to a compressive force and concurrent torsional straining process
leading to grain refinement, often at the nanometer level, with high mechanical strength.
Several processes can lead to a reduction of the pore volume under pressure such as par-
ticle fragmentation and rearrangement, deformation of the zones of contact between par-
ticles until closed porosity is formed, and shrinkage of individual pores. When an external
pressure is applied to packed powder particles, force is exerted on the particle contacts
leading to localized particle deformation. The deformation of the particle contacts under
the action of the effective pressure causes instantaneous plastic yielding of the contact
zone or stress directed diffusion process from the contact area to the pore surface. At rel-
atively low pressure, the diffusion mechanisms tend to contribute more to densification
than power-law creep which, in turn, predominates at high hot isostatic pressure (HIP).
This is because the driving force for the diffusion processes is much less sensitive to the
effective pressure than the rate of dislocation creep. The application of pressure (as a
“driving force”) manifests itself in different ways such as reduced sintering temperature
leading to conservation of grain size and sintering the high-pressure structural phases.
This review focuses on employing pressure as processing parameter to obtain porous bi-
omaterials. Innovative high-pressure processing for porous biomaterials is presented and
the current state of the art for metals, polymers and ceramics is discussed.
2. Discussion on Different Biomaterials

This section discusses various class of materials that are used as porous biomaterials.
2.1. Biodegradable Polymers for Tissue Engineering

Strategies in tissue engineering involve scaffolds, differentiated and undifferentiated
cells and growth factors. Tissue engineering requires scaffolds that are biocompatible, bi-
odegradable, non-toxic and in addition should provide appropriate mechanical support
and adequate surface properties (required for adhesion, proliferation and differentiation
of cells). Among the different options present for scaffolds, polymers are preferred for
their ability to degrade by the enzymes present in the body, minimize inflammatory reac-
tions and non-toxicity. These polymers are classified such as natural polymers and syn-
thetic polymers [7].
Natural polymers are extracted from tissues like collagen and plants. Synthetic pol-
ymers, on the other hand, can be obtained from the polymerization of the monomers. 3D
porous polymer scaffolds play a vital role in the tissue engineering and regenerative med-
icine. Different types of synthetic polymer, such as polylactic acid (PLA) and its copoly-
mers, polylactide-co-glycolide (PLGA) and PLGA-polyethylene glycol (PEG), offer pro-
cessing flexibility and less immunological issues in comparison to the extracellular matrix
(ECM). Various synthetic polymers for biomaterials are discussed in the following section.
2.1.1. Synthetic Polymers for Biomedical Applications

Polyglycolic acid (PGA)—PGA is one of the biocompatible and biodegradable ali-
phatic polyesters that is used for medical applications. Kobayashi et al. [8] reported on the
PGA-collagen nanocomposite which was vascularized within 5 days after implantation in
animal models. Patrascu et al. [9] reported on PGA-hyaluronan (HA) composites on their
chondrogenic potential of implants containing the mesenchymal stem cells (MSCs) in
vitro and in a rabbit articular cartilage defect model. From the literature review it can be
found that PGA composites are suitable as scaffolds for cartilage regeneration and blood
vessels.
Polylactic acid—PLA is a thermoplastic aliphatic polyester, biodegradable and bio-
absorbable with two optical isomers such as L- and D- lactic acid. PLA is widely used in
orthopedic devices, mesh, screws, pins and rods as implants. Lin et al. [10] reported on
the bone regeneration on hydroxyapatite (HAp) and chitosan coated with PLA. Mi et al.
[11] reported on the possibility of using polyurethane (PU) and PLA at different ratios as
the scaffold for the tissue engineering. The PU-PLA at different ratio offered the possibil-
ity to obtain surface roughness, mechanical properties and biocompatibility. PU-PLA pos-
sibility to tune the characteristics apt for soft and hard tissue regeneration.
Polycaprolactone (PCL)—PCL is a biocompatible, bioresorbable and biodegradable
polyester. PCL is used in dental splints, targeted drug delivery and medical implants in
addition to tissue engineering. Zheng et al. [12] reported on the characteristics of PCL
adapted for the use of cartilage and in other tissue regenerations. Other composites of
polyvinyl alcohol (PVA), HAp and PCL nanofibers reported by Uma Maheswari et al. [13]
show the potential of PCL as a biocompatible scaffold for bone and cartilage regeneration.
Poly (lactic-co-glycolic acid)—PLGA is a biocompatible, biodegradable copolymer
that has potential applications in therapeutic tools, tissue engineering and drug-delivery
systems. Junmin Qian et al. [14] studied the influence of PLGA on enhancing the mechan-
ical strength of the scaffolds in the PLGA-nano HAp biocomposite due to the modification
of the crystallinity of the PLGA polymer in the composite. They played a vital role in ini-
tiating osteoblasts essential for bone regeneration.
Poly (N-isopropylacrylamide) (PNIPAM)—PNIPAM is a thermosensitive polymer
with unique physical and chemical applications in tissue engineering for regenerating
damaged bone tissues and in drug delivery. Sa-Lima et al. [15] studied the capacity of
poly (N-isopropylacrylamide)-g-methyl cellulose (PNIPAM-g-MC) as thermo reversible
hydrogel as a 3D scaffold for cartilage regeneration. PNIPAM, when forming composites

with other compounds, can act as a suitable scaffold for tissue engineering applications.
Poly (DL-lactic acid-co-glycolic acid)-g-ethylene glycol (PLGA-g-PEG)—this is a bio-
degradable and bioresorbable polymer that is employed for tissue engineering and in
drug-delivery systems. Sidney et al. [16] reported on the possibility of using PLGA/PEG
scaffolds as localized drug-delivery system for bone regeneration.
Poly (caprolactone/ethylene glycol) (PCL-PEG) copolymer—this is a biodegradable
and biocompatible polymer that has potential applications in tissue engineering. Niu et
al. [17] reported on the possibility of creating a suitable environment for the regeneration
of damaged tissue with the high surface area porosity for cell adhesion and cell differen-
tiation. Based on the animal model chosen, it was inferred that PCL-PEG nerve-guide scaf-
folds had the potential for good peripheral nerve regeneration.
Poly(caprolactone/lactide) copolymer (PCL-PLA)—this is a biodegradable, biore-
sorbable and biocompatible polymer with various applications in tissue engineering.
PCL-PLA copolymer nanofibers were reported to help in regeneration of the damaged
tissue and drug-delivery systems. Karimi et al. [18] reported on the electrospun PCL-PLA
nanofibers containing thymol helping in wound healing.
2.1.2. Natural Polymers for Biomedical Applications

Polymers originating from biological systems such as plants, animals and microor-
ganisms are classified as natural polymers. Natural polymers are employed for various
uses: drug delivery, cosmetics, medical scaffolds and adhesive bandage. Natural poly-
mers are preferred due to their similarity to the host tissue, metabolic compatibility, non-
toxicity and low inflammatory reactions. On the downside, natural polymers have high
temperature sensitivity and are destroyed prior their melting point. Furthermore, there is
high probability to transmit the diseases to human from the natural plant and animal
sources. Currently, two types of natural polymer are employed such as polysaccharide-
based and protein-based. Chitin, chitosan and alginate are well known polysaccharide
based natural polymers. Collagen and gelatin are well-known protein-based natural pol-
ymers [19–21] widely used. A detailed review on the usage of biodegradable polymers
was reported by M. Prakasam et al. [22].
2.2. Porous Bioceramics

Bioceramic [23–25] with porous morphology is interesting owing its possibility to
allow bone tissue growth that leads to fixation of the bioceramic in the implantation site.
Porous bioceramics should have biocompatibility, biodegradability, osteoconductivity
and good mechanical strength. On the other hand, their applications are limited to non-
load bearing bones, fillings and as coating for metallic implants due to their brittle nature,
low ductility and poor degradation rate. Β-TCP, which has higher degradation rate in the
body than HAp, is combined with different polymers to make a composite that has low
fracture toughness. Coating of polymer on the porous bioceramics is one of the methods
to improve porous bioceramics mechanical properties. Miyazaki et al. [26] and Miao et al.
[27] reported on the improvement of compressive strength of porous bioceramics with
silk protein on α-TCP and PLGA on HA/TCP composite, respectively. Microporosity and
nanoporosity present in the bioceramics has a strong influence on their biological re-
sponse such as protein adsorption, cell adhesion and permeability of the biomaterial to
the physiological fluids. Bioceramics with osteogenic and antimicrobial properties by in-
corporation of copper, zinc and silver was investigated [28]. The possibility of incorporat-
ing copper, strontium, zinc, cobalt, boron and silicon improved the osteogenesis property.
Porous bioceramics of CaPs fabricated at low temperature offers the possibility to incor-
porate active therapeutic molecules. By changing the textural property of this porous bi-
oceramic, it is possible to controlled drug-delivery systems or other bone morphogenetic
proteins and growth factors. The morphology of the pore and their shape had an influence
on the cell behavior for cartilage regeneration. Spherical pores with low permeability had
enhanced matrix production and gene expression in vitro compared to cube-shaped pores
[29].
2.3. Bioactive Glasses

Bioactive glasses (BG) are considered as attractive materials for biomedical applica-
tions. Materials consisting of calcium, phosphorous and silicate are classified as BG. The
first BG developed was 45S5 [30]; this material is widely used for bone graft applications.
BGs are also known for their ability to facilitate osteoblast proliferation and differentiation
for bone regeneration. Other types of BG are glass ceramics (S53P4) and borate-based
glasses (19-93B3). The biocompatibility of these BGs is dependent on the quantity of sili-
cate component (45–52%) and for initiating the bone grafting process. Interfacial bonding,
formed either by degradation or dissolution of activate osteogenesis, is strong in BGs. Bo-
rate bioactive glasses are known to degrade faster than silicate bioactive glass; 45S5 BG is
osteoconductive and also osteoinductive. BGs with added polymers are used for bone tis-
sue regeneration such as soft-hard tissue interfaces which have complex tissue structure
defects. Gelatin-BG scaffolds shows vascularization of the cells in the scaffold pores
demonstrating their ability to support cell growth [31]. BG-chitin and BG-chitosan nano-
composites porous scaffolds, prepared by lyophilization with pores in the range of 150–
300 µm, demonstrated in vitro behavior with osteoblast like cells showing the adhesion
of cells to the pore walls [32]. Other BG-polymer composites, such as PDLLA, P(3HB),
PLGA, and PCL-gelatin, showed the possibility of using these BGs as bone regenerative
material with good osteoblast adhesion. BG scaffolds are fabricated by various methods
such as the one pot synthesis method, melt quenching, sol-gel synthesis, cetyltrime-
thylammonium bromide (CTAB), polyurethane sponge template method and 3D printing.
Porous BGs are fabricated also by sintering. This requires high temperature and 45S5 has
a small interval between the glass transition temperature, and the crystallization temper-
ature makes the glass stability region narrow leading to a decrease of mechanical strength
of the scaffold.
2.4. Metallic Biomaterials

Very well-known metallic [33] biomaterials are stainless steel, magnesium, titanium,
and tantalum which are widely employed for various biomedical applications. Iron based
alloys such as Fe–Mn, Fe–P are investigated as biodegradable materials for applications
in stents and as bones. Fe alloys provide the required mechanical property and corrosion
rate. SS 316 L is a well-known alloy that is used for joint replacement, bone plates and
screws. Co–Cr alloys are biocompatible and have high corrosion and wear resistance.
These alloys are used in manufacturing of surgical implants, stents and in dental and bone
implants. Co–Cr–Mo [34] alloys and carbide dispersed Co alloys are used in hip joints. Ti
alloys with aluminum and vanadium were previously widely used. Currently, Ti alloys
[35] with tantalum, tin, niobium and zirconium are used based on their non-cytotoxicity,
good corrosion resistance and biocompatibility. Ni–Ti alloys with their shape memory
properties are used for applications in orthodontic wires, dental bridges, self-expanding
stents and in prostheses. Porous Ta alloys [36] are bioactive and are used as coatings and
for non-load bearing orthopedic applications. Alloys of Mg [37] with Zn, Zr, Zr-Ru, Pt and
Pt alloys, gold and gold alloys both in porous and dense form are used for tissue-engi-
neering applications.
2.5. Porous Scaffold Fabrication Methods

Complex architectures of porous scaffolds for tissue engineering are a field that war-
rants more investigation for innovative fabrication methods. Scaffolds employed in tissue
engineering have high porosity and are biodegradable, non-toxic and should aid in cell
differentiation. Different methodologies are commonly employed in scaffold fabrication
such as solvent casting, freeze drying, gas foaming and electrospinning. Recently, with
the advances in manufacturing technology, innovative high-pressure processing called

freeze isostatic pressure [38] has been used for fabricating scaffolds for a high porous body
with increased mechanical strength. The aforementioned scaffold manufacturing technol-
ogies [39–43] are discussed in detail here.
2.5.1. Solvent Casting

Solvent casting involves casting the solute from the solution by dipping the mold
into it and giving it enough time to dry/evaporate to form the solute layer. This method is
disadvantageous due to the use of toxic solvent which denatures the protein. Here, the
polymer is dissolved in the solvent containing uniformly distributed salt particles of spe-
cific size and the solvent is evaporated leaving behind the matrix with uniformly distrib-
uted salt particles. The salt particles are then leached out to obtain uniform pores. To avoid
the influence of solvent on the polymer, the samples are processed and dried in vacuum
conditions to eliminate the solvent. The samples thus obtained have porous structure.
2.5.2. Freeze Drying

This technique involves the production of porous scaffolds by a sublimation process.
The solute and solvent are mixed according to the required concentration and then frozen.
The ice crystals formed during the freezing process creates the porosity, which are then
subjected to lyophilization under high vacuum. The pore size and the shape can be altered
based on the pH and freezing rate. The samples thus yielded have controlled porosity and
3D pore structure but lack high mechanical strength. On the other hand, this process does
not involve utilization of high temperature and controlled solidification in the single di-
rection to create uniform homogeneous pore structure.
2.5.3. Gas Foaming

This technique employs high-pressure CO2 gas to create the porosity in the scaffolds.
The porosity and its structure depend on the amount of gas used. CO2 gas at high pressure
saturates the polymer with gas, causing the dissolved CO2 to be unstable and it separates
from the polymer forming pore nucleation. These pores then decrease the polymeric den-
sity by expansion of polymeric volume. This technique does not involve usage of organic
components or a requirement of high temperature.
2.5.4. Electrospinning
Currently, electrospinning is a widely used technique for producing continuous fi-
bers in submicron to nanometer scale range. Nanoparticles mixed with polymers are elec-
trospun to produce scaffolds. This technique involves the assembly of nanoparticles
through the alignment of fibers and reduce the Gibbs free energy. No functionalization
process is required and it is dependent on high electrostatic forces. Various factors such
as solution viscosity and flowrate, electric field intensity, work distance and air humidity
play a role in the fabrication of scaffolds.
2.5.5. Three-Dimensional Printing

Three-dimensional (3D) printing is currently most used for fabricating porous ceram-
ics with the possibility to customize the design and size of the pores. Surgical tools, cus-
tom-made prostheses, dental porcelain, and porous ceramic filters are a few examples of
the possibilities of the products made by 3D printing. Three-dimensional printing tech-
nology for porous ceramics gives increased flexibility and rapidity as a low-cost sustain-
able product fabrication alternative. Generally, there are various hindrances in fabricating
the porous ceramics such as pore network interconnectivity, poor reproducibility, thin
structures and time-consuming processes with the conventional fabrication techniques.
Three-dimensional printing offers the possibility to obtain custom-made porous ceramics
with computer-assisted design thus providing provisions to make complex porous struc-
tures. The porous structure formation by 3D printing can be precisely altered with control
of microstructure and optimization of parameters.
2.5.6. Other Processing Techniques

Various other processing routes [44–46] such as replica, sacrificial template and direct
foaming methods are available for the production of macroporous scaffolds. The polymer
replica technique can give open porous structures with pore sizes in the range of 200 µm
to 3 mm and the percentage of porosity varies between 40% to 95%. The downside of this
technique, however, is the weak mechanical strength occurring during the pyrolysis of
the polymer. The wood structure replica technique is the well-known ancient technology
used for obtaining porous scaffolds with highly oriented open pores in the range of 10–
300 µm with porosities in the range of 25–95%. The manufacturing cost and presence of
open pores on the cell walls and high anisotropy are the drawbacks of this technique.
Sacrificial templating is also another technique used in the fabrication of macroporous
samples. This method involves the removal of the sacrificial template through pyrolysis,
evaporation or by sublimation. The slow removal of the sacrificial phase, on the other
hand, increases the sample processing time.
2.6. Pressure-Assisted Porous Scaffolds Fabrication

This section discusses the various pressure-assisted porous fabrication techniques.
However, techniques such as electric current assisted sintering, hot pressing, microwave
sintering and pressure-less sintering are not discussed in this review, as they are exten-
sively reviewed elsewhere [47]. Pressure can act as a driving force for diffusion, enhance
plastic deformation and improve particle rearrangement for consolidation of materials.
Enhancement of hardness and mechanical strength were achieved by severe plastic defor-
mation through grain size refinement. High-pressure torsion (HPT) [48] is one of the well-
known techniques to induce large strains under high hydrostatic pressure. This technique
is mostly used for consolidation of ceramic, metallic and amorphous materials or even
composites [49]. The cold welding process is achieved through application of isostatic
pressure on metallic powders arising from their ductility leading to densification by plas-
tic deformation. In the case of compounds such as ZrO2 and Al2O3, high pressure does not
induce any plastic deformation due to the repacking of grains under applied pressure.
Recently cold sintering has been used for consolidating materials either in porous or dense
form [50]. The various mechanism perceived for the cold sintering is attributed to particle
dissolution and reprecipitation, plastic deformation and hydrothermal-type process [51–
56]. Various high pressure processing techniques used for materials processing are given
in Table 1 [6,53,57–76], mainly at elevated temperature for various level of pressure re-
garding the technologies used.
Table 1. High-pressure processing techniques used for materials processing.
High Pressure Acrony T P*

Equipment (Tool) Applications Material Processing
Processes ms (°C) (MPa)
High Hydrostatic
Pascalization, decontamination, sterilization,
Pressing High HHP
Tank, autoclave disinfection of biological materials (Foods, 20 xxx
Vessel Pressure HPP
Pharmacology, Medical)
(Force Processing
isostati Cold isostatic
CIP Tank, vessel Compaction of powder 20 xxx
c) Pressing
Freeze Isostatic T<
FIP Vessel Consolidation of powder xxx
Pressing 0 °C
Autoclaving
Decontamination, sterilization, disinfection in
(Steam Autoclave, tank 132 P < 1
medical
sterilization)
HyCG
High Pressure Reactor, autoclave, Hydrothermal Crystal Growth Hydrothermal
HyCr 1000 xxx
(isostatic) bomb, vessel Crystallization Hydrothermal Purification
HyPu
Hot Isostatic
HIP Tank, autoclave, bomb Compaction of powder, sintering 1000 xxx
Pressing
Reactive
Infiltration of permeable green compacts by
Hydrothermal unkno
rHLPD Autoclave aqueous solutions + reaction under 240
Liquid-Phase wn
hydrothermal conditions
Densification
Hydrothermal Sintering of powder by hydrothermal
Reaction- HRS Sealed capsule oxidation of a metal + diffusion of H2 from the 900 xxx
Sintering capsule + sintering of the oxide powder formed
Non Leak-proof set-
Uniaxial Pressing up: die, chamber,
UP Compaction of powder 20 xxx
(ambient T) mold, cylinder,
pelletizer
Hydro Pressure
HyPS(≈
Sintering Leak-proof set-up Compaction of powder, consolidation 20 xxx
HyS)
(ambient T)
Cold Sintering
CSP
Process Non leak-proof set-up Compaction of powder, consolidation 20 xxx
(20 °C)
(ambient T)
High-pressure Anvils in rotation
HPT Pre-compaction & subsequent consolidation 20 GPa
torsion while pressing
Uniaxial pressing Non Leak-proof set- Compaction of powder by Uniaxial pressing +
Piston – PUA 20 xxx
ultrasonic up: mold simultaneous powerful ultrasonic action
cylinde
Uniaxial Hot Chamber = Non leak-
r (Force
Pressing (dry UHP proof set-up (Heating Sintering of powder 1000 xx
on 1
materials) by Induction RF exists)
axe)
Autoclave (2
Uniaxial Hot HyS CSP openings) = Leak-
500
Pressing (humid (T > proof set-up (Heating Sintering of powder Sintering of powder xxx
200
materials) 20 °C) by Induction RF exists)
Non leak-proof set-up
Autoclave (2
Hydrothermal HHP
openings) = Leak- Sintering of powder 250 xxx
Hot Pressing (=HyS)
proof set-up
Oscillatory
Non leak-proof set-up:
pressure OPS Sintering of powder 1300 xx + x
Graphite die
sintering
HP-HT,
High Pressure Belt, Bridgman Sintering of powder 1800 GPa
HP-SPS
Multi-
Ultra-high Multianvils (1 stage: 3
anvils
pressure UHPS axes, 2 stages : Kawai, Sintering of powder 2200 GPa
(Force
sintering Walker, ..)
on
multi
axes)
The porous structure can be obtained by applying pressure for short time duration
and/or lower temperature compensated by higher pressure (acting as driving Force) in
these HP processes after the initiation of the necks, to avoid densification.
2.6.1. Isostatic Pressure at Negative Temperature: Freeze Isostatic Pressure

Cold isostatic pressure (CIP) performed on hydrated CaCO3 leads to consolidation of
powders at room temperature [66]. In presence of water, this consolidation was presumed
to occur either by a dissolution/precipitation process or by plastic deformation. The dis-
solution is favoured between the grain contacts, where the stress concentration is high
with the liquid interface layer while external force is applied to the grain. The precipitation
of the dissolute particles resurfaces in the low stress zone. This process is similar to what
happens in hydrothermal sintering process. As for metallic powders, in the presence of
solvent, plastic deformation occurs. The presence of liquid is necessary for consolidating
the materials under high pressure and low temperature. The presence of pressure in-
creases the effect of surface energy to cause diffusion to occur. A similar phenomenon can
be considered for snow deposited on the glacier surface which then transforms into firm
ice. D.S. Wilkinson [77] studied pressure sintering theory on ice. Based on the study of ice,
at low applied pressure, lattice diffusion dominates the temperature but as the pressure
is increased, or under yield stress, plastic flow occurs rapidly.
Formation of a neck is due to the presence of pressure between the ice crystals; dif-
fusion and plastic flow is evident in nature from phenomena observed in glaciers. To un-
derstand ice crystal behavior under pressure, it is essential to know about the phase dia-
gram of water (Figure 1). In 1912, Bridgman [78] reported five different crystalline forms
of ice comprising from type I-IV and VI. Among these, type I ice exists in solid form at
atmospheric pressure and has low density compared to other types of ice crystal. With the
increase in pressure, type I ice shows a decrease in melting temperature up to −22 °C at
200 MPa. When water is transformed into type I ice, their volume increase. In accordance
to Le Chatelier’s principle, the increase in pressure causes a decrease in temperature as
pressure opposes the increase in volume from the formation of type I ice.
Figure 1. P-T diagram of water and their corresponding densities [78].
Above 200 MPa, the slope of melting temperature curve is positive. Above 600 MPa,
ice forms exist above 0 °C hence freezing is possible at ambient temperature. It is known
that compressibility of water is around 8% at 200 MPa and 14% at 400 MPa. By controlling
the temperature, it is possible to change the morphology and the size of the ice crystals as
observed in pressure assisted freezing and thawing widely applied in food sciences. At
low temperatures, activation energy for power law creep is larger, in comparison to lattice
diffusion, and grain growth is slow. When porosity concentrations are low, the driving
force decreases and the lattice diffusion from grain boundaries to the pores is dominant.
Figure 1 shows various pathways possible for the formation of ice crystals along with their
densities. Crystallization and melting not only depends on the pressure level and temper-
ature range but also on pressurization and depressurization rates. Control of temperature
and the heating/cooling rate is complicated in an autoclave. Recently, in the case of freeze
isostatic pressure (FIP), Largeteau et al. [63] have developed an innovative technique,
which could be defined as a CIP process at minus temperature. This innovative technique
called freeze isostatic pressure (FIP) consists of the application of pressure at minus tem-
perature on a mixture made of powder and pure water (solvent by using mineralizer).
Water is used as a template under solid state as ice which is removed at ambient pressure
and temperature. In the FIP process, the ice crystals nucleation/growing of water can be
controlled. Water used as porogen is removed by sublimation. Prakasam et al. [63] worked
on using ice as a template as a porogen (ecological, and safely eliminated from sample)
and apply the pressure simultaneously to consolidate the materials. By selecting the ap-
propriate P and T, it is possible to preserve the integrity of the biomaterial containing
water through formation of ice crystals. Additional parameters such as rate of compres-
sion, decompression, freezing and thawing, determine pore size formed by the ice crys-
tals. The dissolution localized at grains contact favored by a high stress contact point acts
like the dissolution and precipitation processes hypothesized in a hydrothermal sintering
(HyS) process. The transportation of species along the grain boundary, in the lesser stress
contact point, leads to a precipitation on the grain surface and initiates the neck formation
in the free spaces between grains, acting like an osmotic pressure effect. Blackford et al.
[79] explained this phenomenon in the sintering of ice crystals by transportation. In our
case, FIP could be explained by the process where inside the meltwater pressure created
at the sliding interface between ice crystals and SiO2 particles. The frictional heating gen-
erated by the external force on the mixture (powder SiO2 + water), was followed by the
dissolution of SiO2 particles (even if it is low for the chosen temperature) inside this melt-
water layer surrounding the ice crystals in contact with particles of SiO2. Moreover, SiO2
precipitation take place where the constraint is lower by the diffusion between the parti-
cles of the meltwater which presents higher mobility than the ice crystals under pressure,
and the meltwater deposits SiO2 dissolute. Finally, the meltwater freezes inside the free
space where the frictional heating does not exist because it is low stressed. The formation
of ice templating could be formed inside the mixture by deep-freezing inside a deep-
freezer at T < −50 °C rapidly before applying the FIP process for consolidation. The deep-
freezing leads to the formation a homogenous and finely crystallized ice inside the mix-
ture.
In summary, we can assume that a hydrothermal reaction is “any heterogenous
chemical reaction in the presence of a solvent (whether aqueous or non-aqueous) under
liquid state at pressure greater than 1 atm in a closed system”. As the solvent is under
liquid phase, even negative temperature could enhance dissolution and precipitation by
pressure at the contact point of the grains. This consolidation between grains could be also
enhanced by adding binder such as collagen, gelatin, polymer (ex: PVA), and so on. Figure
2 shows the FIP ICMCB equipment.
Figure 2. Freeze isostatic pressure equipment at ICMCB.
2.6.2. Isostatic Pressure at Positive Temperature

A pressure exerted by a static liquid or gas propagate is equal in all directions. The
material to be compacted is brought into a flexible tube and introduced into a liquid or
gas medium. On this medium, a certain pressure is applied so that this pressure acts
equally in all directions of the areas of the form. Thus, the material is multidirectional
compacted and the compaction of the resulting material is based on the compressibility of
the material. Isostatic pressing techniques [80] are classified based on the tool design, tem-
perature and pressure transfer medium used. Cold isostatic pressing (CIP), which is un-
dertaken at ambient temperature, is generally used as a compacting step and requires a
subsequent process of sintering to hold the particles together. After compaction by CIP,
the sample is called as “Green body”. In hot isostatic pressing (HIP), the material under-
goes compacting and sintering, simultaneously. HIP yields higher green bodies densities
than other conventional die-pressing techniques. The green body obtained is more uni-
form and the stresses are not created in the body. Some tensile or compressive stresses
may appear depending on the movement of the mold displacement that may occur during
non-isostatic compaction. Gas isostatic hot pressing without a mold is used to obtain ma-
terials with lesser porosity. Under high gas pressure the open porosity is prevented from
closing. Capsule free/mold free hot isostatic pressure yields an open porous body. HIP
can be applied after all conventional sintering methods in order to improve the mechani-
cal strength and to reduce the pore size. Under high gas pressure, the surface diffusion is
enhanced. Under high pressure, the densification is delayed due to the decrease in the
driving force of sintering by enhanced surface diffusion compared to other conventional
sintering. Due to well grown necks, HIPed porous materials have high mechanical
strength, narrow pore size distribution and high fluid permeability. At high pressure, gas
leads to higher density than by gas at a low pressure or under vacuum. HIP enhances the
neck formation of the pores and the necks enlarge with little densification leading to an
increase in their mechanical strength with narrow pore size distribution and high fluid
permeability. HIP porous materials have potential application as biomaterials, filters,
grinding wheels, porous detectors for electrochemical analysis.
2.6.3. Gas-Reinforced (GASAR) Technique

This technique is the abbreviation of “gas-reinforced” (Gas + Armirovat (reinforce—
in Russian)). This technique [81] involves unidirectional solidification of gas supersatu-
rated melt through eutectic point. Due to their higher gas solubility in the liquid phase,
solidification of the metal and nucleation of gas pores occurs simultaneously leading to
the formation of an ordered gas-eutectic composition. This phase transformation is very
similar to the conventional eutectic reaction. Gas-reinforced metal matrix composites is
also known as lotus type or ordered porosity materials, as no evident gas eutectic for-
mation is evidenced. The major advantages of this technique are its improved strength,
control of pore shape and orientation, flexibility to yield ordered regular structures, gas
and liquid permeability, wide range of pore diameter (from 10 µm up to 10 mm) and ease
of fabrication at low cost. Based on the nature of the metal, the formation of pores during
solidification is higher due to higher gas solubility and shrinkage phenomenon than in
the solid phase. Gas supersaturation in the melt is a prerequisite for the formation of the
pores in GASAR. A mixture of active gases if hydrogen or nitrogen and neutral gases such
as argon or helium is used in GASAR to have flexibility for formation of porous structure.
Usage of neutral gases, due to their insolubility in metal melts, affects the pressure in the
gas pores thus help to control the pore size and porosity concentration inside the body.
Various metal and alloys were used in this technique to fabricate porous metals, alloys
and intermetallics (Al, Be, Cr, Cu, Fe, Mg, Mn, Mo, Ni, Ti, Cu-Al, Al-Si, Ni-Al, Ni3Al, TiNi,
steels and Fe). The porosity formed in this technique is located at the solid–liquid inter-
face. The possibility of porosity range in this technique depends on the gas diffusion co-
efficient and gas solubility in the melt. The pore direction is perpendicular to the moving
solidification front and the porosity is strongly dependent on partial gas pressures during
melt saturation and solidification and the pore diameter is sensitive to solidification ve-
locity.
2.6.4. Hydrothermal Sintering (HyS)

In 1972, the conventional hot pressing in the presence of water in the hydrothermal
conditions was defined as hydrothermal sintering. The objective of this technique is to
densify and consolidate, in a confined pressure medium (such as autoclave), at lower tem-
perature and in the presence of pressure and solvent. This process offers the flexibility to
consolidate dense, porous and layered monoliths. Dissolution and reprecipitation in the
presence of solvent and pressure is the process that governs consolidation rather than the
solid diffusion process observed in other conventional techniques. The hydrothermal pro-
cess (if not aqueous solvent: solvothermal) is a deviation of chemical principle of hydro-
thermal crystal growth (HyCG) used for synthesis of single crystals of alpha-quartz SiO2.
Hydrothermal conditions favored a chemical reaction at low temperatures due to the ef-
fect of subcritical or supercritical state of the hydrothermal fluid. Pressure is exerted from
a combination of (1) external uniaxial force applied by a hydraulic press which is localized
and high at grain contacts and (2) autogeneous hydrostatic pressure caused by the expan-
sion of the solvent in the autoclave which is isostatically surrounding each grain, follow-
ing Kennedy’s abacus. The gradient of pressure between grain contacts and inter grains
partially or full of water (or solvent in the case of presence of mineralizer) in undercritical
(UCF) or supercritical (SCF) state depends on pressure and temperature (P&T) employed
during consolidation. The transportation of the species, from the high-stress contact point
to the less-stress contact point, will initiate the neck formation through precipitation. This
process is based on parameters such as pressure, temperature, state of fluid to judge dis-
solution and the solvent/mineralizer used. Duration of the hydrothermal reaction also
plays the main role in the consolidation process of HyS. By varying the pressure and the
temperature, it is possible to sinter the desired phase such as for example amorphous-
amorphous or amorphous-crystallized phase. Thus, this innovative HyS process [82] of-
fers the possibility to obtain ceramics of alpha-quartz SiO2 with amorphous precursors of
silica at lower temperature than phase transition temperature of alpha-beta quartz SiO2
which occurs at 573 °C and ambient pressure. Other examples of materials consolidation
by HyS are hydrated composition (ex: HAp), porous or dense microstructure, and low
chemical reactive compounds such as SiO2 and TiO2.
2.6.5. Thermosensitive Materials Processing with High Hydrostatic Pressure

The current state of the research field on biocomposites are synthetic materials which
are used for repair, replace and/or create an interface between the biological environment.
Recent advances in fabrication processes allow the possibility of incorporating active ma-
terials such as drug-delivery systems. To date, various radiation sources such as gamma,
ultraviolet (UV), e-beam, ion beam was widely used for biocomposites to decontaminate.
Usage of polymers as packaging substances is very well known and the decontamination
of these biocomposites is undertaken conventionally by irradiation technique. However,
the radiation can react with the crosslinking properties of polymers resulting in radical
changes of their various functional properties. Another potential alternative innovative
technique that can be employed is high hydrostatic pressure (HHP) processing, which is
discussed in the present work. In the early 1990s, HHP processing was mainly developed
for food to diminish microbiological decontamination to improve shelf-life for consump-
tion. At present, HHP is an emerging technology with widespread applications in Biosci-
ences, including pharmaceutical products, cosmetics and medicine. Non-thermal decon-
tamination, in particular cold decontamination, using pressure treatment, permit the in-
herent property of the material (food, drug, cream, biomaterial, etc.) to be preserved. The
main applications of HHP technology are decontamination at temperature below the
usual temperature applied in pasteurization (called also appertization) and at the same
time it aids preservation of the inherent properties such as vitamins, color, taste, and
smell, texture in foods and on raw materials.
The HHP process consist of a closed high-pressure vessel filled with fluid acting as a
transmitting media compressed by pump or by diminishing the volume of the vessel, to
apply isostatic pressure. HHP are beneficial aspects includes preserving the therapeutic
efficiency of drug in pharmaceutical products and for decontaminating biomaterials in
particular for polymers which are thermosensitive. Other promising applications of HHP
are that it is foreseen is to decontaminate and/or to impregnate some porous biocomposite
with inorganic structure such as thermosensitive polymers (collagen, hydrogel) for de-
contamination; in other words, decontaminating thermosensitive biocomposites packed
in flexible polymer film to avoid direct contact with pressure transmitting media. With
the assistance of HHP the packaging surrounding the material to be decontaminated,
transmits the pressure homogenously. With such potential applications, it is of high com-
mercial and clinical importance to evaluate HHP processing as a decontamination, up to
a sterilization, method at temperature compatible with the stability of sensitive compo-
nents required for better functional activity. Properties of biocomposite constituted by
thermo-responsive hydrogel with a nano/micro encapsulated complex-drug delivery sys-

tem mean that HHP processing can be a potential new method of decontamination for
medical and biocomposites materials. These materials which are sensitive to the currently
existing decontamination processes such as gamma irradiation or high temperature meth-
ods for a wide range of biocomposites.
2.7. Examples of Porous Silica and Porous Copper by Innovative High-Pressure Processing
Silica-based bioactive glasses are used successfully for different bone defects and soft
tissue engineering. Silica-based glasses are widely preferred as a biomaterial, but due to
the lack of mechanical properties their clinical applications are limited. Silica-based glass
is touted to be a third-generation biomaterial for bone tissue regeneration. Silica-based
mesoporous materials can be an excellent candidate for controlled drug delivery systems
and grafting material for bone regeneration. Macroporous SiO2 bioactive scaffolds are re-
quired for osteoblast proliferation. Jones and Hench developed 3D bioactive macroporous
scaffolds which have poor fracture toughness and pore strength. In the present work we
have reported on porous SiO2 scaffolds by freeze isostatic pressure (FIP) and this process
allows the scaffold and incorporate therapeutic drug molecules to be decontaminated at
the same time during fabrication process. Our innovative equipment allows a porous
structure of biocomposites (inorganic structure with thermosensible polymer or therapeu-
tic molecules as an example) to be obtained with as a second effect a decontamination
(called as sanitization) at low temperature, called cold decontamination (also called Pas-
calization) by the HPP process.
2.7.1. Freeze Isostatic Pressure (FIP) Processing of Amorphous SiO2

The FIP experiment was undertaken on AlfaAesar amorphous spherical SiO2 powder
(ref: L16987) with 1.5 µm diameter to manufacture monoliths of porous silica such as bio-
material model which could contain pharmaceutical molecules, mainly destroyed at tem-
perature beyond human corporal temperature. We mixed 0.5 g of AE-SiO2 powder with
190 µL NaOH-2M at 1500 bar for 3 h. The choice of the amount of powder and the solvent
is important for the study of the material. An excess of solvent will make the pellet brittle
and more powder will increase the thickness of the pellet; too thick a pellet is of no interest
in testing which is also limited by the volume of the mold. To form a pellet, graphite mold
containing the mixture of SiO2 + NaOH-2M was placed at −80 °C in the deep-freezer for
minimum 1 h (Figure 3). The frozen mixture was then unmolded and sealed quickly inside
packaging. The FIP experiment was carried out under the following conditions: the sealed
pellet was re-placed in the deep-freezer at −80 °C for 1h, and the pellet was immersed in
the pressure transmitter fluid at −40 °C inside the vessel of FIP. The pressure of 1500 bar
was applied immediately and held for 3 h. This pellet presents 45% porosity (Figure 4).
Figure 3. Tomography (internal diameter cut view, diameter: 10 mm) of the sample consolidated by
freeze isostatic pressure (FIP) showing a non-uniform distribution of pores and inhomogeneous
repartition of solvent (presence of agglomerates).
Figure 4. Tomography (internal diameter cut view, diameter = 10 mm) of the sample consolidated
by FIP showing an uniform distribution of pores by increasing the content of solvent.
Tomography analysis allowed us to visualize how the distribution of the solvent is

not homogeneous in the powder because there are agglomerates. The increase of solvent
quantity led to an increase of porosity, as illustrated in Figure 4. An improvement in me-
chanical strength was achieved by evaluation: like powder (not reported), impossible to
handle (friable, not reported), possible to handle but fragile (−), not breaking by falling 1
m (+). We observed that pressure was increased from 1500 bar to 2300 bar (Figure 5). The
pressure, therefore, does not influence the porosity and the strength of the pellet, but it
has a beneficial effect on the mechanical strength.
Figure 5. Porosity as a function of various parameter of FIP process.

FIP experiments show that porosity is related to the volume of solvent used for pre-
paring the solution (Figure 5), and with the increase of solvent the porosity increases. Po-
rosity was greatly influenced by the freezing time for making the ice crystals. With the
increase of pressure the FIP process yielded a good mechanical property.
2.7.2. Hydrothermal Sintering of Porous Amorphous SiO2

This HyS process will help for the improvement of consolidation phenomena in com-
parison with FIP process with the help of temperature above 20 °C. The temperature will
increase the dissolution, but the precipitation has to be driven to select the amorphous
form, by avoiding the crystallized form which is not biocompatible. The example given
below concerns the use of PLA particles as a template to form porous structure after its
elimination inside the mixture of AE-SiO2 + PLA; PLA is a biodegradable polymer. The
final composite AE-SiO2 + PLA could be also used like biocomposite.
We used 0.5 g of amorphous SiO2 from Alfa Aesar (AE-SiO2) for fabricating porous
samples with mechanical property after evaluation by: not breaking by falling 1 m (+), and
resistant to manual fracture (++).
The porosity study was carried out by adding to the mixture (0.5g AE-SiO2 + 140 µL
NaOH-2M) different amounts of particles of PLA sieved at 100–500 µm. This biodegrada-
ble polymer melts at 150 °C for easy disposal. The study was done at 250 °C to avoid
crystallization of the amorphous SiO2, which leads in a denser material if the PLA is not
added. A second treatment was at 200 °C for 2 h in hydrothermal fluid by using conven-
tional HP vessel with pure water, to eliminate the PLA still present in the pellet by disso-
lution (Figure 6).
PLA 50mg
Figure 6. Porosity of AE SiO2 by hydrothermal dissolution.
The Figure 7 shows that the porosity is low if the force is high because high pressure
induces high compactness. The pellet with the lowest porosity value (4.49%) was synthe-
sized at 370 °C for 2 h at 12 kN (1500 bar), leading to complete crystallization, as this is the
stability domain of the quartz phase. This high temperature induces a greater dissolution
of the PLA. The pellets synthesized in the field of stability of the amorphous phase at low
forces (0.1 kN (12 bar) and 0.5 kN (100 bar)) exhibit high porosity but low mechanical
strength (friable). On the other hand, the pellet synthesized at 1 kN (127 bar) has both high
porosity (40.7%) and very good mechanical strength (not brittle). The content of PLA af-
fects also the mechanical behavior but is compensated by the force applied.
Figure 7. Porosity as a function of temperature in hydrothermal sintering.
2.7.3. Hydrothermal Sintering of Porous Spherical Copper

Copper was used in the form of particles inside ceramics for antibacterial action and
improvement of synthetic bone graft substitutes [4]. Then, copper was studied as a metal-
lic biomaterial model based on the well-defined particles.
The copper powder used had spherical copper grains with a diameter of the order of
50 to 100 μm. Spherical copper is very difficult to compact because the spherical shape
does not help with intergranular cohesion. The mechanical strength after uniaxial press-
ing with 1 g of spherical copper powder was very poor with compression forces varying
between 0.4 t and 3 t for a period of 5 min at room temperature. Above 3 t, the pellets may
stay in place but collapse after removal of pressure. Water was added as a binder for
spherical copper particles, but they still could not stay in place. Copper and water form a
heterogeneous mixture (poor wetting of the beads) hence we chose to use PVA (polyvinyl
alcohol) with a mass concentration of 50 g/L (powder dissolved in water) as a binder. The
samples thus obtained had good mechanical resistance after uniaxial compaction. Fur-
thermore, the pellets were compacted by cold isostatic pressure to increase the mechanical
strength. With the increase of force, compactness increases. Porosity of 35% was obtained
at 1.2 t and temperature of 350 °C with 7 µL PVA for a dwell time of 2 h.
The hydrothermal sintering process consists of applying an initial pressure of be-
tween 6 and 40 MPa with a rise in temperature to 370 °C, maintained for 2 h on the Cu +
H2O mixture (Figure 8). A porosity of 40% was obtained. The variation of porosity was
observed with respect to the initial pressure applied (Figure 9).
Figure 8. Microstructure of porous Cu samples obtained by hydrothermal sintering.

Figure 9. Variation of porosity with respect to initial applied pressure in Cu porous samples by
hydrothermal sintering.
These results obtained show the advantage of high pressure in obtaining porous sam-
ples by innovative high-pressure processing. The sections described in 2.6 and 2.7 can be
employed with any kinds of biomaterial ranging from metals, polymers, composites and
to therapeutic compounds. As high-pressure techniques at low temperatures (FIP, CIP
and HyS) can be used for sterilization of the fabricated samples, these techniques at high
pressure and low temperature can be employed for clinical applications.
3. Summary and Outlook

Porous scaffolds are indicated for tissue engineering in restoring bone defects. The
porous scaffolds help cells to attach, proliferate and differentiate to form a desirable new
tissue. Various parameters such as composition, structural features such as porosity, pore
size and morphology play a vital role in obtaining tissue engineering. The pores and their
morphology are essential in judging their mechanical and biological performances. The
degree of porosity influences their performances in vitro and in vivo. Several processing
techniques are available for fabricating porous biomaterials in the form of polymers, com-
posites, metals and ceramics. Very well-known techniques are gel casting, slip casting,
freeze casting and foam/replica methods, electrospinning and in addition to conventional
sintering techniques and 3D printing. Pressure and temperature are two thermodynamic
parameters essential in engineering the microstructure with controlled porosity and mor-
phology. Various pressure-based innovative techniques are used for fabricating porous
scaffolds. Amongst the well-known methods are GASAR, hot isostatic pressure and hot
pressing. In recent years, hydrothermal sintering and freeze isostatic pressure have of-
fered possibilities to obtain porous scaffolds of polymers, metals, composites and ceramics
at low temperature and high pressure. These innovative techniques can be employed on
materials that are susceptible to phase changes at high temperature and for thermosensi-
tive components. FIP allows the possibility to incorporate active therapeutic molecules in
the porous scaffolds at low temperature and simultaneously disinfect the scaffold to be
directly used for in vitro and in vivo applications. The hydrothermal sintering process
helps to obtain biomaterials either in compact or in porous forms at relatively low tem-
peratures in comparison to other sintering techniques.
By considering the influence of the processing parameters on the pore morphology

and mechanical properties, high-pressure processing methods through hydrothermal sin-
tering and freeze isostatic pressure techniques offer a new processing route for fabricating
porous biomaterials. We have demonstrated the possibility of obtaining the porous bio-
materials of amorphous SiO2 and Cu spheres by high-pressure processes. From our point
of view, future work in this field should aim at tuning the processing parameters to obtain
the desired microstructure and open interconnected porous biomaterials. By addressing
the aforementioned points, it is possible to obtain porous biomaterials at high pressure
with increased mechanical strength at low temperatures. Processing at low temperatures
and high pressure will be an attractive option for materials that have OH components in
their structure and thermosensitive materials. Furthermore, this will help to incorporate
therapeutic molecules or other active molecules for targeted drug delivery. FIP and hy-
drothermal sintering for porous biomaterials is relatively new, and further detailed inves-
tigations on these innovative pressure processing methods will be very helpful in produc-
ing low-temperature porous biomaterials with increased mechanical strength.
In summary, the action of a solvent under pressure (hydrothermal) induces consoli-
dation by dissolution-precipitation, even at minus temperatures, in order to initiate the
intergranular cohesion or by using a template (ex H2O in FIP or PLA in HyS process).
These high-pressure processes such as CIP in the presence of solvent, FIP and HyS could
be applied to the manufacture of a biocomposite containing thermosensitive materials
such as biopolymer (e.g., PLA) or pharmaceutical molecules.
Author Contributions: A.L. contributed to conceptualization, methodology, investigation, re-

sources, supervision, writing-review and editing and project administration. M.P. contributed to
investigation, formal analysis, data curation, validation and writing-original draft preparation. J.-
F.S. contributed to investigation and formal analysis. All authors have read and agreed to the pub-
lished version of the manuscript.
Funding: This research received no external funding.
Acknowledgments: The authors thank Oudomsack Viraphong for his help in the fabricating essen-
tial high-pressure elements. The authors thank Stéphane Toulin for his assistance with bibliography.
Conflicts of Interest: The authors declare no conflict of interest.
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Innovative High-Pressure Fabrication Processes for Porous

Academic Editor: Mark Edward

Bioengineering 2021, 8, 170. https://doi.org/10.3390/bioengineering8110170 www.mdpi.com/journal/bioengineering

thermodynamic parameter that can help in fabricating porous biomaterials obtained at

2. Discussion on Different Biomaterials

2.1. Biodegradable Polymers for Tissue Engineering

2.1.1. Synthetic Polymers for Biomedical Applications

hydrogel as a 3D scaffold for cartilage regeneration. PNIPAM, when forming composites

2.1.2. Natural Polymers for Biomedical Applications

2.2. Porous Bioceramics

2.3. Bioactive Glasses

2.4. Metallic Biomaterials

2.5. Porous Scaffold Fabrication Methods

the advances in manufacturing technology, innovative high-pressure processing called

2.5.1. Solvent Casting

2.5.2. Freeze Drying

2.5.3. Gas Foaming

2.5.5. Three-Dimensional Printing

2.5.6. Other Processing Techniques

2.6. Pressure-Assisted Porous Scaffolds Fabrication

Table 1. High-pressure processing techniques used for materials processing.

High Pressure Acrony T P*

2.6.1. Isostatic Pressure at Negative Temperature: Freeze Isostatic Pressure

Figure 1. P-T diagram of water and their corresponding densities [78].

Figure 2. Freeze isostatic pressure equipment at ICMCB.

2.6.2. Isostatic Pressure at Positive Temperature

2.6.3. Gas-Reinforced (GASAR) Technique

2.6.4. Hydrothermal Sintering (HyS)

2.6.5. Thermosensitive Materials Processing with High Hydrostatic Pressure

thermo-responsive hydrogel with a nano/micro encapsulated complex-drug delivery sys-

2.7.1. Freeze Isostatic Pressure (FIP) Processing of Amorphous SiO2

Tomography analysis allowed us to visualize how the distribution of the solvent is

Figure 5. Porosity as a function of various parameter of FIP process.

2.7.2. Hydrothermal Sintering of Porous Amorphous SiO2

Figure 7. Porosity as a function of temperature in hydrothermal sintering.

2.7.3. Hydrothermal Sintering of Porous Spherical Copper

Figure 8. Microstructure of porous Cu samples obtained by hydrothermal sintering.

3. Summary and Outlook

By considering the influence of the processing parameters on the pore morphology

Author Contributions: A.L. contributed to conceptualization, methodology, investigation, re-

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