1.4.
7
Textured and Porous Biomaterials
W. BENTON SWANSON, PETER X. MA
Department of Biologic and Materials Science, School of Dentistry, University of Michigan,
Ann Arbor, MI, United States
Introduction
Porous and textured biomaterial features have played an
important role in the success of a myriad biomedical appli-
cations. Both the short- and long-term utility of biomateri-
als in medicine relies on their ability to interface with the
body and deliver functionality without causing harmful
complications. Biomaterial properties, including texture and
porosity, are not only advantageous but necessary to facili-
tate successful biologic integration and influence cell adhe-
sion, infiltration, proliferation, and nutrient and waste mass
transfer. The culmination of favorable cellular responses at
the tissue–material interface leads to organogenesis and
accelerated healing. Biomaterial architectures at various size
scales are key engineering and design considerations which
require innovative fabrication strategies to impart favorable
biologic compatibility to material constructs without com-
promising mechanical and other properties in application-
specific uses.
In the past three decades there have been explosive
advances and interest in porous and textured biomaterials
due to new fabrication methods, particularly due to advances
in the field of tissue engineering (Ma, 2008; Langer and
Vacanti, 1993). As early as the 1940s, textured and porous
features of successful medical devices serve as early examples
of tissue engineering-like approaches to biomaterials fabrica-
tion. Biomaterial surfaces serve as critical interfaces between
host and implant to coordinate many biologic processes. As
demonstrated in recent literature and commercial medical
products (Fig. 1.4.7.1), there is a strong appreciation for
biomaterial architectural features, including surface texture
and porosity, as advantageous design criteria. Hence, reliable
and tunable fabrication methods are critical to the advance-
ment of biomaterials science. Not intended to exhaustively
review all textured and porous biomaterials, this chapter will
focus on synthetic biomaterials and their tunable nano-,
micro-, and macroscale architectures covering the following
areas: (1) porous and textured synthetic matrices currently
used in medical devices, (2) a comparison of the breadth
of fabrication methods for biomimetic features to achieve
desirable properties, and (3) a discussion of novel process-
ing technologies and recent advances in combining multiple
fabrication technologies, with more examples from recent
advances such as in tissue engineering applications. 
Importance of Texture and Porosity in
Facilitating Biomaterial Integration
Historically, materials with textured and porous morpholo-
gies have higher success rates than smooth constructs. The
extent of a construct’s success is heavily related to its ability
to facilitate tissue ingrowth, prevent fibrosis, and promote
angiogenesis of surrounding tissue. Of these three, tissue
ingrowth—physical integration of the material into the
host—is the most important. A host’s natural response is to
encapsulate an implant with a fibrous capsule to compart-
mentalize it from the rest of the body, which is minimized
by textured implants and open pore architectures, leading to
the formation of a thinner foreign-body capsule (Salzmann
et al., 1997). Numerous materials can be textured or ren-
dered porous, including metals, ceramics, and natural and
synthetic polymers. We will discuss specific examples of
successful biomedical devices and their material features.
Textured Devices Promote Healing and
Restore Organ Function
Dental implants, made of titanium and metal alloys as well
as soft material constructs, benefit from textured surfaces.
Their success in restoring normal mastication is directly
related to their ability to integrate with craniofacial bone
through the process of osseointegration. Branemark et  al.
defined osseointegration as the direct structural and func-
tional connection between ordered living bone and the
surface of a load-bearing implanted construct (Branemark,
1983). Mechanical interlocking between a synthetic proth-
esis (titanium dental implant) and the living bone is criti-
cally important and can be facilitated by intentional surface
texture (Esposito et  al., 2005). This idea launched the
601
602 SEC T I O N 1 . 4     Materials Processing
development of surface-modified implants to increase the
osteoinductive potential of their surfaces (Dohan Ehrenfest
et al., 2010). Macrotopography of implants can be designed
in a variety of ways, strategically interfacing with local neo-
tissue to facilitate implant integration. Additional visible
geometries such as ledges, flutes, indentations, and grooves
influence integration and are shown to increase implant sta-
bility and long-term success. These morphologies are pri-
marily created by milling processes (Buser et al., 2012).
Microscale structures may also enhance the process of
bone healing. Increased surface roughness has been shown
to increase success by influencing cell and tissue integration.
It also enhances interfacial and shear strength, important
for dental implants to withstand the forces of the oral cavity
over time (Strietzel et al., 2004; Wennerberg and Albrekts-
son, 2000). Increasing the surface area of the implant,
through texture and roughness, allows greater space for cells
to attach and facilitate tissue neogenesis around the implant.
Microscale structures are influenced by techniques includ-
ing acid etching, anodization, sandblasting, and grit blast-
ing to mechanically impart features (Dohan Ehrenfest et al.,
2010). More recently, laser micromachining has been used
to modify dental implant surfaces (Nevins et  al., 2010).
Buser et  al. evaluated the outcomes of 511 sandblasted,
large grit, acid-etched dental implants (Straumann) in 303
patients over 10 years, and reported a success rate of 97%,
with 98.8% of implants surviving 10 years without com-
plication. For patients, advances in dental implant design
allow for more rapid loading and return to normal lifestyle.
Breast augmentation surgeries are one of the most com-
mon cosmetic surgical procedures in the United States
(Benediktsson and Perbeck, 2006; Gampper et al., 2007);
• Figure 1.4.7.1 Biomaterial architectural scales at multiple levels are
important considerations for developing fabrication methods.
(A)
• Figure 1.4.7.2  Examples of porous hydroxyapatite (A, left) and polyethylene (A, right) orbital implants;
sagittal view of human orbit showing placement of orbital implants in the eye socket (B).
15%–25% of breast implant procedures are complicated by
fibrous capsular contraction and result in long-term con-
tracture, due to the body’s natural response to any foreign
object (Taraballi et al., 2018). Fibrous capsule contracts in
the months following implantation leading to patient dis-
comfort and disfigurement, and ultimately implant failure.
Implant surface texture (smooth vs. textured) is known to
be a key factor influencing success (Howard, 1999; Bur-
khardt, 1984; Burkhardt et al., 1986).
Orbital implants (Fig. 1.4.7.2) compensate for lost tissue
when the eye is enucleated due to severe trauma, intraocu-
lar cancer, or removal of a blind and painful eye (Chalasani
et  al., 2007; Sami et  al., 2007). Key engineering consid-
erations include fit, motility, and minimized long-term
complications such as extrusion, migration, and infection
(Goldberg et  al., 1994). A variety of materials, including
glasses, silicones, and acrylics, have been used in orbital
implants; recently, porous materials such as hydroxyapatite
(HAP) and polyethylene (PE) have shown increasing popu-
larity. Their textured structure roughly resembles native
surrounding trabecular bone, and thus encourages fibrovas-
cularization of the implant within a few weeks compared to
implants with smooth surfaces (Chalasani et al., 2007; Sami
et al., 2007). These advantages influence patient outcomes
by increasing healing rate and decreasing infection, leading
to therapeutic success in compensating for lost tissue.
The cellular mechanisms of texture are not completely
understood. Evidence suggests that texturing influences col-
lagen arrangement of the surrounding extracellular matrix.
Irregularly arranged collagen fibers at the textured surface
may be less likely to create cooperative contractile forces and
are more susceptible to collagenase degradation ­(Pennisi,
1990). Textured implants also show increased local macro-
phage number, which may degrade the capsule as it forms
(Taylor and Gibbons, 1983). Additionally, texture mini-
mizes micromotion and reduces chronic inflammation. In
the case of breast implants, factors including the type of tex-
turing, pore size, or implant material do not appear to be as
important as simply disrupting surface smoothness (Caffee,
1994; Danino et al., 2001). 
Porosity to Promote Tissue Ingrowth
Synthetic vascular grafts used to repair damaged or
occluded blood vessels are a good example of necessary
(B) Bone
Conjunctiva
Orbital Extraocular
Implant Muscles
Artificial
Eye
Bone
 CHAPTER 1.4.7   Textured and Porous Biomaterials 603

pores in biomaterial constructs. Pores are critical to support
mass transport for cells and tissues and facilitate integra-
tion, both of which contribute to accelerated healing. In
general, porous architectures must be sufficiently large to
facilitate cell and tissue infiltration, while small enough to
prevent fibrotic tissue formation and minimize interfacial
cell necrosis from mechanical shear forces (Sharkawy et al.,
1998; Rosengren et al., 1999). For vascular grafts, porosity
helps to facilitate the formation of a stable, endothelium-
lined lumen to provide an antithrombotic surface similar to
native vessels (Wesolowski et al., 1961; White et al., 1983;
Clowes et  al., 1986; Zhu et  al., 2009; Ma et  al., 2010).
Numerous studies demonstrate that highly porous small-
diameter grafts have superior healing and long-term success
compared to low-porosity grafts (Hess et al., 1984; Golden
et al., 1990). Porosity allows for the ingrowth of fibrovascu-
lar tissue and infiltrating capillaries, which facilitate endo-
thelialization and smooth muscle cell growth along the graft
surface.
Macro- and microscale pores imparted to biomaterial
constructs are similar to the porous organization of many
physiologic tissues, such as bone (Fig. 1.4.7.3). Trabecular
and cortical bone are both porous, up to 50%–90% and
3%–12%, respectively. In cortical bone, Haversian canals
allow for fluid flow, which supports metabolism; pores in
trabecular bone support the bone marrow that contains
stem cells (Cooper et al., 2004; Lanyon and Baggott, 1976).
Materials used to restore orthopedic function must be
osteoconductive and capable of vascularization (Stevens,
2008; Gupte et al., 2018). Porous metals are one example
of orthopedic implants, which allow bone healing and high
osseointegration, similar to the dental implants mentioned
earlier (Matassi et al., 2013). Highly porous metals can be
fabricated from many elements, including tantalum, tita-
nium, titanium alloy, and other alloys. Baril et al. quanti-
fied tissue response to porous metal orthopedic implants
by microcomputed tomography and hard tissue histology
techniques, and demonstrated that interconnected pores at
the implant surface significantly improve osseointegration
(Baril et al., 2011).
Critical to the success of these implants and a com-
mon theme in many implants, tissue ingrowth around and
within the construct increases the likelihood of integration
and long-term success and minimizes the risks of rejection.
Advances in titanium porous foam manufacturing show
mechanical properties similar to cancellous bone (Matassi
et al., 2013). A variety of manufacturing technologies exist
that allow for controlled porosity, including solid free-form
machining, molding, stereolithography, laser machin-
ing, and sintering (Lewallen et  al., 2015). These material
modifications have a dramatic effect on clinical outcome
by facilitating cell and tissue ingrowth (osseointegration)
and bone formation (osteoinduction), particularly in hip
and knee arthroplasty (replacement) procedures (Hanzlik
et al., 2013). A challenge with porous metallic foams, such
as those used in orthopedic applications, is their mechanical
properties, since increasing the amount of void space within
the construct decreases its stiffness and fatigue strength.

(A) (B)

(C) (D)

• Figure 1.4.7.3  Porous structure and composition of coralline hydroxyapatite (A), human cancellous bone
(B), and macroporous, nanofibrous PLLA scaffolds fabricated by pore leaching and TIPS demonstrate well-
interconnected, spherical pores (C, scale = 500 μm) with a nanofibrous surface texture (D, scale = 2 μm).
PLLA, Poly(l-lactic acid); TIPS, thermally induced phase separation. (Modified from Wei, G.B., Ma, P. X.,
2006. Macroporous and nanofibrous polymer scaffolds and polymer/bone-like apatite composite scaffolds
generated by sugar spheres. J. Biomed. Mater. Res. A 78A (2), 306–315.)
604 SEC T I O N 1 . 4     Materials Processing
 Biomaterials for Tissue Engineering
Considering these examples of textured and porous syn-
thetic materials in biomedical applications, it is important
for engineers to develop a toolkit of fabrication strategies
to achieve desirable nano-, micro-, and macrolevel mate-
rial features. In the context of tissue engineering, there is
no single ideal construct; scaffolds are typically designed
for specific applications. Important factors in tissue-engi-
neering scaffold design include the selection of a biode-
gradable and biocompatible polymer that degrades at a
rate that matches tissue neogenesis, architectural features
and mechanical properties specific to the target tissue that
it aims to replace, with a surface that facilitates adhesion,
proliferation, and differentiation of cells, and a network
for nutrient exchange and diffusion (Zhang et al., 2016b).
Texture and porosity address the latter needs. Advances
in materials processing strategies, which allow for con-
trolled design at the nanometer and micrometer scales, are
reviewed in the following sections.
 Fabrication Methods for Biomimetic
Nanoscale Texture
The purpose of a tissue-engineering scaffold is to serve as an
artificial extracellular matrix (ECM), which spatially supports
cells, facilitates cell adhesion, provides topological cues and
mechanical support (Boyan et al., 1999; Ito, 1999). Thus it is
reasonable to fabricate a tissue-engineering scaffold that mim-
ics the fibrous proteins in the ECM found in nearly all tissue
types. Collagen is the most abundant extracellular protein in
the human body, with a triple helix macrostructure and sub-
micrometer fiber diameter (50–500 nm) (Hay, 1991; Elsdale
and Bard, 1972). Collagen is a natural polymer and can be
used as a scaffolding material, but significantly lacks process-
ing control particularly in regards to mechanical properties,
degradation rate, batch-to-batch consistencies, and pathoge-
nicity (Ma and Zhang, 1999). Synthetic polymers lend them-
selves to the highest degree of processability and tunability
(Ma and Elisseeff, 2005). Poly(l-lactic acid) (PLLA) and
poly(lactic-co-glycolic acid) (PLGA) are poly(aliphatic esters)
and are the most commonly used biodegradable polymers
because they degrade on a biologically relevant timescale, and
are approved for biomedical use by the US Food and Drug
Administration (Bergsma et al., 1995; Ma and Choi, 2001;
Peter et al., 1998). A list of the most common biodegradable
synthetic polymers is shown in Table 1.4.7.1. Electrospin-
ning, self-assembly, and thermally induced phase separation
are well-exploited processing technologies for achieving an
ECM-like nanoarchitecture and surface texture in synthetic
biomaterials, each with unique properties and applications,
as summarized in Table 1.4.7.2.
Electrospinning
Electrospinning originates from the textile industry as a
method of generating fibers using an electric field (Morton,
1900; Anton, 1934). Electrospinning imposes a difference
in electrical charge between a needle and substrate to draw
fine fibers from a polymer solution droplet. Electrodes
between the polymer-charged needle and substrate create an
electric potential, and the resulting electric field ejects a jet
of polymer. The volatile organic solvent that dissolved the
polymer evaporates to leave behind a polymeric nanofibrous
or microfibrous mesh (Fig. 1.4.7.4). Current advances in
electrospinning technology are working toward thinner
fiber diameters, most similar to the native ECM (Liu et al.,
2017).
Electrospinning has proven effective for making fibers
with a variety of natural and synthetic biodegradable poly-
mers, including collagen (Matthews et al., 2002), chitosan
(Bhattarai et al., 2005), silk (Min et al., 2004), poly(glycolic
acid) (Boland et al., 2001), PLLA (Yang et al., 2005), PLGA
(Li et al., 2002; Kim et al., 2003), and poly(caprolactone)
(Yoshimoto et al., 2003), as well as nonbiodegradable poly-
mers (Kenawy el et al., 2003; Smith and Ma, 2004). Cells
are able to survive, proliferate, and differentiate to a vari-
ety of functional phenotypes on electrospun nanofibrous
or microfibrous materials (Li et  al., 2003; Pham et  al.,
2006a,b). Electrospun nanofibrous matrices are easy to fab-
ricate into two-dimensional (2D) sheets and meshes; how-
ever, three-dimensional (3D) constructs are difficult. It is
hard to fabricate complex scaffold shapes, a critical crite-
rion for fabricating biologically relevant tissue-engineering
scaffolds. Additionally, it is difficult to incorporate an inter-
nal porous network. Construct porosity is intimately con-
nected to nanofiber properties; in certain size ranges, it is
hard to independently control fiber size and pore size/shape
(Table 1.4.7.3). 
Self-Assembly of Nanoscale Features
Broadly, self-assembly is defined as the autonomous orga-
nization of components into patterns or structures without
intervention (Whitesides and Grzybowski, 2002). Spe-
cific to nanofiber engineering it is the rational design and
chemical modification of synthetic polymers to organize
into ECM-like structures. Noncovalent macromolecular
bonding dictates multidimensional structures, includ-
ing: hydrogen bonding, van der Waals forces, hydro-
phobic interactions, and electrostatic interactions (Lehn,
2002a,b). Self-assembly is advantageous for engineering
very small diameter fibers (<100 nm) by exploiting ratios
of copolymer section lengths with different properties.
The result is self-aggregation of a 3D structure, which
mimics the ECM-protein triple helix on a smaller scale
(Ramachandran, 1988). Biology offers countless examples
of self-assembly; this technology draws from the self-
assembling nature of proteins into secondary and tertiary
structures, and phospholipid macrostructures (Whitesides
et al., 1991).
Synthetic peptide amphiphiles have been synthesized to
mimic the ECM-protein triple helix, with a short peptide
head sequence connected to a long lipid chain tail. Their
TABLE
1.4.7.1    Classes of Biomaterials and Methods to Render Texture in Medical Devices and Tissue-Engineering Applications

Material Methods to
Class Specific Examples Render Texture Advantages Disadvantages
Synthetic polymers In order of decreasing degradation rate: Discussed in detail, • Can be made to mimic • No biologic specificity
(Karageorgiou and • Poly(glycolide) (Reed/Gilding, Polymer, 1981; Ma/Langer, Tables 1.4.7.2 natural extracellular matrix • Lack direct functionality
Kaplan, 2005; Simske Mat. Res. Soc., 1995) and 1.4.7.3 • Tunable degradation kinetics
et al., 1997; Ryan • Poly(lactide-s-glycolide) (Pitt/Langer, Biodegradable • Tunable processing lends
et al., 2006) Polymers as Drug Delivery System, 1990) itself to rational design
• Poly(lactide) (Eling, Polymer, 1982; Zhang/Ma, J. Biomed. • Recent facile processing
Mater. Res., 1999) technologies
• Poly(dioxanone) (Barrow, Clin. Mater., 1986; Barber, • Feasible to produce on large
Orthopaedic Special Edition, 1998) scale
• Poly(trimethylene carbonate) (Barrow, Clin. Mater., 1986; • Nonimmunogenic
Barber, Orthopaedic Special Edition, 1998) • Support cellular proliferation,
• Poly(caprolactone) (Pitt, Biomaterials, 1981) migration, differentiation
Additional examples:
• Poly(ethylene glycol)
• Poly(vinyl alcohol)
• Poly(ethylene terephthalate)
• Poly(urethane) (Lin, J. Biomed. Mater. Res., 1994)
• Poly(phosphoesters) (Wang, JACS, 2001)
• Poly(phosphazenes) (Caliceti, Int. J. Pharm., 2000; Aldini,
J. Orthopaedic Res 2001)
• Poly(anhydride) (Leong, Biomaterials, 1986)
• Poly(orthoesters)/poly(orthocarbonates) (Choi, Patent
4,093,709 1978)
• Poly(glycerol sebacate) (Loh, J. Mat. Chem. B, 2015).

CHAPTER 1.4.7   Textured and Porous Biomaterials

Natural polymers • Collagen • Can be made to mimic • Lack mechanical
(Karageorgiou and • Hyaluronic acid natural extracellular matrix strength
Kaplan, 2005; Haarer, • Silk fibroin • Biodegradable • Rapid degradation rates
2008; Ott et al., 2008) • Gelatin (Choi, J. Biomed. Mater. Res., 1999) • Amicable for • Immunogenic and
• Alginate (Shapiro, Bioimaterials, 1997) biofunctionalization rejection potential
• Chitosan (Madihally, Biomaterials, 1999) • Support cellular proliferation, • Degradation not tunable
• Decellularized extracellular matrix (Steve Badylak, Probst, migration, differentiation • Difficult processing
BJU Int., 2000; Ott/Matthiesen, Nat. Med., 2008; Guyette, • High cost
Circulation Res., 2015; Gershlak, Biomaterials, 2017)
Composite materials • Hydroxyapatite-coated poly(l-lactic acid) (Liu/Ma, Ann. • Porosity from • Combine biomimetic/ • Complex fabrication
Biomed. Eng., 2004; Wei/Ma, Biomaterials, 2004; Du, J. synthetic osteoconductive ceramic protocols
Biomed. Mater. Res., 1999) component properties and processability
of synthetic polymers

(Continued)

605
 606 SEC T I O N 1 . 4     Materials Processing
 
TABLE
  Classes of Biomaterials and Methods to Render Texture in Medical Devices and Tissue-Engineering Applications—cont’d
1.4.7.1 

Material Methods to
Class Specific Examples Render Texture Advantages Disadvantages
Ceramics • Hydroxyapitite • Plasma spray • Similar compositions and • Low resorption rate
(Sun et al., 2001; • Natural coral • Sintering structure to natural bone • Brittle mechanical
Karageorgiou and • Calcium phosphate • Enhanced osseointegration properties
Kaplan, 2005; Simske • Amorphous glasses and osteoconductivity using • Difficult to control
et al., 1997) apatite-like materials porosity
• Biocompatible • Not amenable to large-
• Low corrosion scale production
• Bind some growth factors • Lack biodegradability
(i.e., BMP, LeGeros, Clin. (Maquet/Jerome, Mater.
Orthop. Rel. Res., 2002) Sci. Forum, 1997)
Metals • Titanium and Ti alloys • Plasma spray • Bioinert • Corrode over time
(Sun et al., 2001; • Cobalt-chromium and Co-Cr alloys • Sintering • Strong mechanical • Stress shielding in vivo
Karageorgiou and • Tantalum • Grit blast properties, less susceptible from high Young’s
Kaplan, 2005; Simske • Wire mesh to fatigue modulus
et al., 1997; Ryan • Combustion • Ideal for implants • Lack biodegradablility
et al., 2006; Bobyn synthesis (Maquet/Jerome, Mater.
et al., 1999) • Vapor deposition Sci. Forum, 1997)
 CHAPTER 1.4.7   Textured and Porous Biomaterials 607

TABLE
1.4.7.2    Fabrication Methods for Nanofibrous and Textured Synthetic Polymer Matrices

Method Description Advantages Disadvantages

Electrospinning Electrostatic force is used to
draw a polymer solution into
fibers through a capillary
Self-assembly Polymer is designed to
autonomously organize into
cylindrical fibers based on
noncovalent interactions
Thermally Decreasing system temperature
induced of a polymer solution causes
phase a polymer to phase separate
Separation from its solvent resulting in a
nanofibrous polymer matrix
• Reproducible
• Applicable to wide range of
polymers
• Easily fabricates 2D constructs
• Biomimetic fiber structure
• Tunable fiber structure based on
polymer composition
• Fiber diameters are most
similar to Type I collagen (native
extracellular matrix)
• Scalable
• Minimal equipment investment
• Applicable to both 2D and 3D
fabrication
• Equipment investment required
• Fiber diameter is larger than Type
I collagen
• Difficult to create 3D construct
• Polymer synthesis is labor
intensive
• Fiber diameter is smaller than
Type I collagen
• Not scalable
• Requires careful solvent choice
(gelation temperature is critical
parameter)
• Requires certain degree of
polymer crystallinity

• Figure 1.4.7.4  Schematic of electrospinning equipment used to create large-diameter nanofibers. A poly-
mer solution is drawn into fibers when an electric potential is applied between the syringe needle and a
substrate (A); the resulting nanofibers have average diameters on the micron scale (B, scale = 20 μm).
(Adapted from 2014. RSC Adv. 4, 13652–13661.)

morphologies are governed by changes in pH and solu-
tion activity, which modulate electrostatic forces. While
these supramolecular fibers are shown to support cellular
activity, they do not have the same bulk structure as ECM
proteins (Fields et al., 1998; Yu et al., 1999). Hartgerink
et  al. used this strategy to fabricate peptide amphiphile
nanofibrous cylindrical micelles. These nanofibers are, on
average, 5–8 nm in diameter and about 1 μm in length
(Hartgerink et al., 2002). Others have formed biomimetic
beta-sheet structures with two distinct surfaces—polar and
nonpolar—by self-assembly of ionic self-complementary
oligopeptides. Upon exposure to alkaline cations, these
sheets self-assemble to a nanofibrous hydrogel, which
facilitates neuronal cell attachment and differentiation
(Holmes et  al., 2000). Similarly, multidomain synthetic
peptides have been shown to self-assemble into nanofi-
brous hydrogels and elicit favorable cell responses toward
angiogenesis and neurogenesis (Moore et  al., 2018). Sci-
entifically, self-assembled nanofibers are interesting. Com-
plicated chemical syntheses and potentially high cost can
achieve lowest end diameters of synthetic polymer nano-
fibers. These self-assembly techniques are largely used to
make hydrogel matrices.
 Thermally Induced Phase Separation
Thermally induced phase separation (TIPS) requires mini-
mal equipment and achieves fiber diameters most similar to
the native ECM. Phase separation occurs when a multicom-
ponent system becomes thermodynamically unstable under
certain conditions and separates into a multiphase system
to lower its free energy (Ma et al., 2016). Originally used in
the preparation of porous polymer membranes, it has since
been used to fabricate porous tissue-engineering scaffolds
(Zhang and Ma, 1999b) with ECM-mimicking architecture
(Zhang and Ma, 2000; Peter and Ma, 1998; Wei and Ma,
2004).
In this scaffold fabrication technique, thermally induced
phase separation is utilized to fabricate the nanofibrous scaf-
folds through the following five steps: (1) polymer dissolu-
tion in an organic solvent, typically tetrahydrofuran (THF)
but other solvents are reported (Zhang and Ma, 2000), (2)
phase separation and gelation induced by low temperature,
(3) solvent extraction, (4) freezing, and (5) freeze drying
under vacuum (Wang et  al., 2007). The critical gelation
step separates the solution into polymer-rich and polymer-
lean phases, which control the morphology of the resulting
608 SEC T I O N 1 . 4     Materials Processing

TABLE
1.4.7.3    Methods for Fabricating Porous Synthetic Polymer Scaffolds for Tissue-Engineering Applications

Method Description Advantages Disadvantages

Porogen leachinga Polymer solution is cast in preformed • Depends on porogen choice • Porogen and polymer
(Mikos et al., 1994) porogen template; porogen leaching • Possible to have large solvent compatibilities are
results in 3D macropores amount of control over a key parameter
pore size, shape, and
interconnectivity
• Open pore architecture
Salt leaching • Easily leached by water • Nonspherical
• Low degree of connectivity
Paraffin leaching • Spherical pores of well- • Requires organic solvents
controlled size to leach paraffin
• High interconnectivity • Residual paraffin is
and tunable degree of cytotoxic
interconnectivity
Sugar leaching • Spherical pores of well-
controlled size
• High interconnectivity
and tunable degree of
interconnectivity
• Easily leached with water
Phase Separation Gelation of crystalline material induced • Good mechanical properties • Lacks control over pore
(Ma and Zhang, by low temperature, below a critical • Oriented structures are shape or interconnectivity
1998) gelation temperature. After solvent possible (Ko and Ma, 2012;
evaporation, nanofibrous matrices Zhang and Ma, 1999a,b)
remain.
3D printinga Computer-aided design and • Reproducible • Limited resolution for
(Sachs et al., 1992; manufacturing used to fabricate a • Macroarchitecture and 3D nanoscale features
Wu et al., 1996; porous scaffold by direct printing of shape are tunable to fit • Choice of material is limited
Yang et al., 2001; polymer or to print a scaffold mold anatomy, can be patient
Chen et al., by reverse solid freeform fabrication specific
2006b)
Fiber Bonding Physical bonding of nonwoven • Large surface area • Lacks mechanical strength
(Mikos et al., 1993) polymer fibers to create an • Difficult to control porosity,
interconnecting mesh no control over shape
Emulsion freeze Polymer solution is homogenized with • Open pore architecture • Difficult to control
drying water, quenched, and freeze dried • Aqueous phase can internal morphology—
(Whang et al., 1995) be used to incorporate pore size, shape, and
bioactive molecules interconnectivity
Self-assembly Self-assembly of graphene oxide • Allows for integration of • Synthetically involved
(Nie et al., 2017) produces macrostructure based on functional moieties for compared to other
electronic aggregation improved biointegration (i.e., methods
osteoconductive)
Sintering Thermal annealing of microspheres • Pore interconnectivity is • Difficult to control pore
(Borden/Laurencin creates an internal 3D controlled shape
J. Biomed. Mater. interconnected porous network
Res., 2002)
Gas foaminga High-pressure gas dissolved to • Fast processing • Lacks control over pore
(Mooney 1996) supersaturation in polymer solution • No organic solvents shape
to create pores required • Pores are not
interconnected (closed
pore architecture)
aDiscussed in this chapter.
 CHAPTER 1.4.7   Textured and Porous Biomaterials 609

(A) (B)

(C) (D) (G)

(E) (F)

• Figure 1.4.7.5 Scanning electron microscopy micrographs of a PLLA fibrous matrix prepared

from 2.5% (wt/v) PLLA/THF solution at a gelation temperature of 8°C at 500× (A, scale = 50 μm) and
20K× (B, scale = 1 μm) magnification, demonstrating nanofibers resulting from TIPS fabrication. Cells
cultured on smooth (C, scale  = 
200 μm; D, scale = 50 μm) and nanofibrous (E, scale  = 
200 μm; F,
scale = 20 μm) matrices for 24 h. Osteoblast cell proliferation is increased on nanofibrous PLLA scaf-
folds compared to smooth scaffolds over the course of 12 days, when both scaffolds are initially
seeded at the same cell density (G). NF, nanofibrous; PLLA, poly(l-lactic acid); SW, smooth walled;
THF, tetrahydrofuran; TIPS, thermally induced phase separation. (Modified from (A,B) Ma, P.X.,
Zhang, R., 1999. Synthetic nano-scale fibrous extracellular matrix. J. Biomed. Mater. Res. 46, 60–72;
(C–F) Hu, J., Feng, K., Liu, X., Ma, P., 2009. Chondrogenic and osteogenic differentiations of human
bone marrow-derived mesenchymal stem cells on a nanofibrous scaffold with designed pore network.
Biomaterials, 30 (28), 5061–5067; (G) Chen, V. J., Smith, L. A., Ma, P. X., 2006b. Bone regeneration on
computer-designed nano-fibrous scaffolds. Biomaterials, 27 (21), 3973–3979.)

nanofibrous scaffold. This step is also dependent on the sol-
vent and polymer properties (Atala and Lanza, 2001; Smith
and Ma, 2004).
PLLA solution undergoes TIPS, and the solvent is
exchanged to leave behind a nanofibrous matrix with fibers on
the same diameter scale as natural ECM proteins, 50–500 nm
(Fig. 1.4.7.5) (Ma and Zhang, 1999; Peter and Ma, 1998).
Interestingly, fiber diameter does not significantly change
with respect to polymer concentration, thermal annealing,
solvent exchange, and freezing temperature. A lower gelation
temperature (i.e., −20°C vs. liquid nitrogen) results in more
well-defined fibers. At a high gelation temperature, platelet-
like structures result (Ma and Zhang, 1999). These matrices
have a porosity up to 98.5%, which allows cells to efficiently
infiltrate the construct and facilitates nutrient exchange; they
have a surface area-to-volume ratio two to three orders of
magnitude higher than fibrous nonwoven fabrics made using
textile technology or foams made with particulate leaching
(Ma and Zhang, 1999). Because of these features, TIPS is an
excellent method for achieving biologically relevant nanofi-
bers in polymer constructs.
The TIPS phenomenon is thought to occur through
spinodal liquid–liquid phase separation, and consequential
crystallization of the polymer-rich phase (Smith and Ma,
2004). The ability to form a nanofibrous matrix depends on
the crystallinity of the polymer, determined by its enthalpy
of melting by thermogravimetric analysis. The nanofibrous
textures of PLGA and poly(D,l-lactic acid) (PDLLA)
matrices are evidently different from PLLA (Fig. 1.4.7.6)
(Ma and Zhang, 1999). The same is noted with many
PLLA-based and other functional copolymers, which must
maintain a certain degree of crystallinity to be able to form
stable nanofibrous structures (Liu and Ma, 2009, 2010; Liu
et al., 2009).
610 SEC T I O N 1 . 4     Materials Processing

• Figure 1.4.7.6  Crystallinity is a critical parameter in TIPS fabrication of nanofibrous matrices. PLLA (A)
forms nanofibrous matrices while PDLLA (B) and PLGA (C) do not (scale = 50 μm). PDLLA, Poly(D,l-lactic
acid); PLGA, poly(lactic-co-glycolic acid); PLLA, poly(l-lactic acid); TIPS, thermally induced phase sepa-
ration. (Reproduced from Ma, P.X, Zhang, R., 1999. Synthetic nano-scale fibrous extracellular matrix. J.
Biomed. Mater. Res. 46, 60–72.)

 Grooves and Micropatterns
In addition to nanofibrous surface architectures, other
grooved and micropatterned textured surfaces have bio-
logic consequences on cell behavior. The ECM is critically
important for organizing cell adhesion; controlling sites
of cell adhesion is one method for modulating cell fate by
geometric means. Capillary endothelial cells were switched
from growth to apoptosis by modulating surface features
of micropatterned substrates, namely so-called “adhesive
islands.” Other factors, including cell spreading and cell
shape, are also controlled by these geometric surface fea-
tures. Decreasing island size restricted cell extension and
induced apoptosis. Chen and others have pioneered this so-
called geometric control of cell fate, which is an enabling
technology to better understand fundamental mechanisms
for 2D tissue microenvironment regulation (Chen et  al.,
1997, 1998; Guilak et  al., 2009). For example, under-
standing mechanisms of angiogenesis—critical to tumor
growth—is important to advancing our understanding of
cancer metastasis.
Micropatterned substrates are fabricated by microcon-
tact printing, which allows for substrate patterning with
regions that are selectively modified. Silicon wafers are
coated with photoresist and exposed to UV light through
a patterned mask. After developing the photoresist, the
pattern is left on the mask, resulting in a substrate that is
appropriate for making a polymer stamp (Singhvi et  al.,
1994). The substrate is stamped with sufficient pressure
to cause contact, and proteins or other biologic molecules
can be adsorbed to the surface to study cell–matrix interac-
tions. Surface micropatterning has been demonstrated as a
means of cell-based assays, as reviewed by Falconnet. This
is a potentially important tool for organizing cells on sen-
sors, as well as for drug discovery and screening applica-
tions (Falconnet et al., 2006).
 Fabrication Methods for Micro- and
Macroscale Architectural Features
Native tissues are organized hierarchically, with incor-
porated channels for mass transport of nutrients, waste,
and signaling molecules, and a spatial organization of
both cell–cell and cell–matrix interactions. In design-
ing synthetic prostheses or tissue-engineering scaffolds, a
biomimetic approach to recapitulating the native porous
architecture is advantageous. Various studies have dem-
onstrated the importance of interconnecting pores in a
number of bone tissue-engineering and other biomedical
 CHAPTER 1.4.7   Textured and Porous Biomaterials 611

• Figure 1.4.7.7  Fabrication process of sugar–porogen template leaching and TIPS, as shown by scan-
ning electron microscopy micrographs. Sugar particles as received (250–425 μm, A) are fabricated into
spherical particles via an emulsion method (250–425 μm, B). A sugar sphere template is heat treated to
form a template for interconnected macropores (C) and polymer solution (PLLA/THF) is cast (D), phase
separated, and solvent exchanged, resulting in a 3D macroporous (E, 50× magnification) and nanofi-
brous (f, 10K× magnification) scaffold. The same method can be modified to use sugar rods stacked in
an orthogonal pattern (G), used to fabricate nanofibrous scaffolds (H) with tubular macropores (I). PLLA,
Poly(l-lactic acid); THF, tetrahydrofuran; TIPS, thermally induced phase separation. (Modified from (A–F)
Wei, G.B., Ma, P.X., 2006. Macroporous and nanofibrous polymer scaffolds and polymer/bone-like apatite
composite scaffolds generated by sugar spheres. J. Biomed. Mater. Res. A 78A (2), 306–315; (G–I) 2000.
J. Biomed Mater Res. 52 (2), 430–6.)

constructs (Wei and Ma, 2006; Zhang and Ma, 1999b;
Klawitter et  al., 1976; Bobyn et  al., 1980; Ryan et  al.,
2006). While optimal pore size depends on the scaffold
and tissue types, there is consensus that a minimum pore
size exists to allow for vascularization, tissue ingrowth,
cell infiltration, and uniform cell distribution (Chalasani
et al., 2007; Gupte et al., 2018). Porous materials are fab-
ricated from synthetic and natural polymers, ceramics,
and metals—each with unique processing methods and
resulting mechanical properties (Ryan et  al., 2006). A
porous 3D construct has a high internal surface area and
void space, providing a substrate for critical cell–matrix
interactions to occur (Fig. 1.4.7.3) (Ma, 2005; Alberts,
2002; Sarkisov, 2012). Porosity considerations include
porosity, pore size (Gupte et  al., 2018), pore shape
(Kawano et al., 2014; Kasten et al., 2008), interpore con-
nections (Chen and Ma, 2004), pore orientation (Ma and
Zhang, 2001), and pore wall surface morphology (Wei
and Ma, 2007). Each of these considerations and their
various combinations require fabrication methods with
high levels of control.
Interconnected Spherical Macropores by
Porogen Methods
Porogen methods are a practical means to easily fabricate
porous biomaterials with consistent macroarchitectural
control, and at a low cost. Porogens are commonly used to
form a template having complex pore architectures within
a polymer solution by reserving free space in the matrix;
once the polymer solvent evaporates and subsequently
the porogen is dissolved, a porous 3D construct remains
(Fig. 1.4.7.7) (Ma and Langer, 1999). Depending on the
desired properties of the final construct, porogens can be
solid, liquid, or gas, albeit liquid porogens are most dif-
ficult but possible in theory. For solid porogens, solvent
choice and porogen/polymer solubility differences require
careful consideration.
In 1991 DePonti demonstrated the first example of a
porogen method using gas foaming—taking advantage of a
gas-phase porogen (CO2), which does not involve harsh sol-
vents or high temperature to impart pores (DePonti et al.,
1991). Porous PDLLA disks having up to 97% porosity
612 SEC T I O N 1 . 4     Materials Processing
were fabricated by saturating a polymer solution with car-
bon dioxide for 3 days (Mooney et al., 1996). The resulting
pores have a closed pore structure and solid exterior skin,
both of which are not conducive to mass transport phenom-
ena. The pores are generally nonuniform and irregularly
shaped in these foams. Recent developments aim at deter-
mining appropriate parameters to achieve a more desirable
pore network using supercritical fluid technology (Bhami-
dipati et al., 2013).
Salt was the first solid porogen and is the most frequently
used method for pore fabrication (Mikos et al., 1994). First,
salt is ground into small particles; particles of desired size
are collected by sieving and packed into a mold. Polymer/
solvent solution is cast over a packed water-soluble salt tem-
plate. Salt leaching technique is discussed thoroughly in the
literature (Ma and Langer, 1999). After the solvent evapo-
rates, the solid polymer is laden with salt particles; soaking
the polymer foam in water leaches away salt crystals, leaving
behind pores throughout the scaffold. Salt particulate leach-
ing can be combined with high-pressure carbon dioxide gas
foaming to increase the size of pores achieved by gas foam-
ing only, which has demonstrated utility in smooth muscle
engineering (Harris et al., 1998). Despite the ease of fabri-
cation, it is difficult to control pore shape (limited to cubic
crystal structure of salt), interconnectivity (limited by nons-
pherical pore shape), and interpore opening size.
To improve on interconnectivity, critical to facilitate mass
transport, a spherical porogen with the ability to be control-
lably fused is necessary. Paraffin spheres are the first example
of a uniformly spherical porogen used in tissue-engineering
scaffold fabrication (Ma and Choi, 2001). Spheres are fab-
ricated by a dispersion method and annealed slightly with
heat treatment in a mold. After polymer casting and solvent
evaporation, a paraffin-laden polymer matrix results. Paraf-
fin is removed in a nonpolar solvent that selectively dissolves
paraffin but not the polymer, leaving behind a porous scaf-
fold with interconnected pores.
Paraffin spheres are easily fabricated; however, it is an
incompatible porogen (soluble) to many organic solvents.
Additionally, its leaching can leave behind trace amounts of
residual hydrophobic porogen that may have unfavorable
consequences to cell activity. Sugar is an excellent alterna-
tive because it is easily processible and can be dissolved by
water (Zhang and Ma, 2000). d-Fructose is emulsified in
mineral oil with a nonionic surfactant, washed and sieved to
desired size ranges (Fig. 1.4.7.7). Sugar is heat treated and
polymer solution is cast. After leaching, scaffolds are highly
porous with well-interconnected macropores and superior
control over interconnectivity. Varied amounts of heat in
the annealing step controls pore interconnectivity; longer
heat treatment results in larger openings between pores (Ma
and Choi, 2001). The compressive modulus of resulting
scaffolds decreases with increasing porosity (Ma and Choi,
2001). Progress has been made in more-interconnected
microchanneled and porous scaffolds by salt leaching (Tran
et al., 2011) and processing salt into round particles to fab-
ricate interconnected pores (Mukhopadhyay et al., 2010).  are advantageous for controlling pore interconnectivity by
Nonspherical Architectural Patterning
Many tissues in the human body are naturally organized
in oriented, tubular, or fibrous bundle architectures. The
anisotropic properties of tissues, including nerve, muscle,
dentin, tendon, and ligament, can be mimicked with care-
fully designed scaffolds (Ma, 2004; Ma and Zhang, 2001).
Pores are incorporated by growing rod-shaped crystals in
polymer solution by inducing phase separation along a uni-
axial temperature gradient. Following TIPS, a network of
aligned nanotubules results. When seeded with MC3T3
preosteoblasts, cells organize along tubular channels to form
an oriented tissue, mimicking the organization of dentin
and long bone (Ma and Zhang, 2001).
Larger oriented pores can be achieved using a tubu-
lar porogen, similar to spherical macropores discussed in
detail in the section Interconnected Spherical Macropores
by Porogen Methods. Melted d-fructose can be drawn
into thin fibers and solidified at room temperature. Their
diameter, on average 100–500 μm, can be controlled by the
drawing rate from melted bulk. Fibers are organized in a
mold to create a porogen frame within a PLLA solution;
after TIPS, sugar fibers are leached by water leaving behind
a network of uniaxially oriented tubular macropores with
a nanofibrous surface texture (Zhang and Ma, 2000). It is
possible to fabricate scaffolds with layered orthogonal or
helicoidally oriented macropores through a layer-by-layer
assembly of fibers of similar diameter in varied orientations.
Pores are interconnected at contacting points of the sugar
fibers. Nonporogen methods for achieving these types of
macroporous architectures are also achieved by 3D print-
ing (Chen et al., 2006b) and by injection molding around
objects such as needles (Sun et al., 2012). 
Combining Multiple Fabrication Methods
A review of the literature supports the importance of nano-
fibrous surfaces that mimic the cellular ECM, and porous
constructs that support diffusion and infiltration. Nanofi-
bers provide a continuous biomimetic fiber network that,
at the cellular level, selectively increases protein adsorption
compared to smooth wall constructs (Woo et al., 2003), and
promotes cellular adhesion and proliferation in a variety of
cell types (Smith et al., 2010; Wang et al., 2011; Liu et al.,
2009). Integrin expression also mediates cell–matrix interac-
tions and may activate pathways like focal adhesion kinase,
which plays a role in cell differentiation (Smith et al., 2009);
nanofibers have been shown to facilitate stem cell differen-
tiation toward multiple differentiation fates depending on
culture conditions and exogenous factors (Hu et al., 2009;
Gupte and Ma, 2012; Subramanian et al., 2009; Hu et al.,
2010a,b; Ahmadi et al., 2011; Liu et al., 2015; Feng et al.,
2012). Scaffolds should also have an internal intercon-
nected porous network that facilitates cellular integration,
uniform cell distribution, vascularization, and nutrient/
waste exchange (Ma, 2008). Uniformly spherical particles
 CHAPTER 1.4.7   Textured and Porous Biomaterials 613

heat treatment. Macropores are particularly important in
cell-free constructs where endogenous cells migrate and dif-
ferentiate to fill a defect (Woo et al., 2009). These 3D tissue-
engineering scaffolds with interconnected macropores have
demonstrated regenerative potentials in a variety of tissues
and physiological systems in as little as 4 weeks. It is critical
for materials scientists and biomedical engineers to consider
fabrication methods that can be combined to have tailorable
biomaterial processing at nano-, micro-, and macroscales.
Macroporous, Nanofibrous
Tissue-Engineering Scaffolds
One example of the success of these constructs is seen in
mineralized tissue neogenesis: odontogenesis of dental pulp
stem cells in vitro and in vivo (Wang et al., 2011; Chatzistav-
rou et al., 2012; Soares et al., 2018), and osteogenic differ-
entiation of multiple cell types, including embryonic stem
cells (Smith et  al., 2009, 2010, Hu et  al., 2010) and bone
marrow stromal cells in vitro (Woo et al., 2009; Hu et al.,
2008). In vivo critical sized calvarial defect models have dem-
onstrated the importance of well-interconnected macropores
for vascularization as well as in supporting endogenous and
exogenous osteoblasts and osteoprogenitor cells (Fig. 1.4.7.8)
(Woo et al., 2009; Hu et al., 2008; Gupte et al., 2018).

Methods such as porogen leaching and TIPS are examples
of two separate fabrication methods that are combined to
yield a favorable combination of surface texture and an
interconnected macroporous network. This has been dem-
onstrated with a variety of porogens, including salt (Zhang
and Ma, 2000), sugar fibers (Zhang and Ma, 2000), paraf-
fin spheres (Chen and Ma, 2004), and sugar spheres (Wei
and Ma, 2006). Porogens are chosen to be cold tempera-
ture insensitive such that polymer solutions can be cast over
them and quickly chilled to gelation temperature, inducing
TIPS to result in a nanofibrous matrix after solvent removal.
Resulting matrices have high porosity (98%) and a high sur-
face area (90–110 m2/g) with biomimetic nanoarchitecture
features suitable for cell attachment, proliferation, and dif-
ferentiation (Wei and Ma, 2006). Sugar is an ideal porogen
because it is completely leached by water.
 Multiphasic Scaffolds
Within a single construct it is possible to incorporate mul-
tiple architectural motifs and multiple variants of the same
motif. For example, in engineering a construct for the repair
of an osteochondral defect it is necessary to consider the
physiologic needs of cartilage and bone tissues, and their
interface. It is unlikely that one scaffold design meets the
needs of two distinct tissue types. However, it is equally
unlikely that two unique cell-scaffold constructs, cultured
separately, then combined, will result in continuous inte-
gration and distribution of cells to form a functional tis-
sue interface (Gao et al., 2001; Alhadlaq and Mao, 2005).
Patterning of architectural features can be used in directed
3D tissue differentiation within a single material construct
(Hu et  al., 2009). One can imagine taking advantage of

(A)

(B) (C)

• Figure 1.4.7.8  Histological images of H&E-stained nanofibrous scaffold implanted in a mouse calvarial defect
for 8 weeks (A, arrow marks site of original defect, scale = 1 mm). Peripheral (B, scale = 100 μm) and central (C,
scale = 100 μm) images show bone tissue neogenesis throughout the scaffold construct. (Reproduced from
Woo, K., Chen, V., Jung, H., Kim, T., Shin, H., Baek, J., Kim, G., 2009. Comparative evaluation of nanofibrous
scaffolding for bone regeneration in critical-size calvarial defects. Tissue Eng. A 15 (8), 2155–2162.)
614 SEC T I O N 1 . 4     Materials Processing

• Figure 1.4.7.9  Computer-aided design/computer-aided manufacturing-designed three-dimensional (3D)

printed tissue engineering scaffolds are advantageous because of their ability to be fabricated in complex
3D macroscale shapes with well-defined features. 3D PLLA scaffolds can be fabricated from reverse solid
freeform fabrication; a negative mold (A) is used for polymer casting, where the solid struts eventually
become open pores in the nanofibrous scaffold (B, scale = 500 μm; C, scale = 2 μm). Computed tomogra-
phy scans can be used to capture topographic features of a human ear (D, E, scale = 10 mm) and mandible
(F, G, scale = 10 mm) in tissue-engineering scaffold. PLLA, Poly(l-lactic acid). (Reproduced from 2006.
Biomaterials 27 (21), 3973–3979.)

the multipotency of bone marrow-derived mesenchymal
stromal cells (BMSCs) to differentiate into osteoblasts or
chondrocytes depending on the environment, and design a
bioinstructive biphasic tissue-engineering scaffold to accom-
modate both tissue types in distinct zones (Caplan, 1991).
 3D Printed Scaffolds
The macroscale shape of 3D tissue-engineering constructs
is often a challenge for repairing clinically relevant large
defects; new technologies in 3D printing can allow for con-
trolled and customizable 3D scaffold shape. The earliest
examples of 3D printed tissue-engineering constructs date
to the mid-1990s (Giordano et al., 1996; Park et al., 1998).
Computer-aided design (CAD) is employed to design scaf-
folds for solid freeform, reverse solid freeform, and rapid
prototyping manufacturing (Giordano et  al., 1996; Yang
et al., 2002; Lin et al., 2004; Smith and Ma, 2012). One
facile method for scaffold fabrication is to print a negative
mold from a material that can later be dissolved (i.e., wax)
by solid freeform methods. The mold can be filled with
porogen, polymer cast, and frozen to induce TIPS. After
dissolving the mold and porogen, a customized 3D scaffold
shape with macroporous and nanofibrous features remains
(Ma, 2004). To make scaffolds customized to a patient
or injury site, a computed tomography scan of the void
to be filled is taken and using CAD software the scaffold
or mold can be printed to an exact fit, for example, man-
dibular bone regeneration following trauma (Fig. 1.4.7.9)
(Chen et al., 2006b). Powder inkjet printing has also been
demonstrated to be feasible, but requires improvements in
efficiency before it is commercially adopted (Butscher et al.,
2011). 3D printing is advantageous because it is highly
reproducible; however, it is currently limited by selection of
materials, which are both biocompatible/biodegradable and
printable, and by pixel resolution of the printers. This area
has potential for significant growth in personalized medi-
cine applications. 
Injectable Tissue-Engineering Scaffolds
To accurately fit an irregular 3D defect site with minimal
intervention, a biodegradable injectable scaffold is ideal,
maintaining nanofibrous and macroporous architectural
motifs. In the last 15 years there has been explosive inter-
est in using micro-/nanospheres in tissue engineering (Wang
et al., 2012). The first example of a microcell carrier was by
Van Wezel in 1967—using dextran microcarriers to support
cell attachment, growth, and proliferation in cell culture
(Van Wezel, 1967). Multiple types of anchorage-dependent
mammalian cells have been shown to thrive in microcarrier
culture (Posillico, 1986; Tang et al., 1994; Freed et al., 1993).
Microspheres provide a unique opportunity for tunability
with control over both their interior and exterior surfaces,

nanofibrous texture, macroporous architecture, and size.
Depending on polymer composition and fabrication proto-
col, a variety of structures can be formed, including nanofi-
brous solid microspheres (Liu and Ma, 2010), nanofibrous
hollow microspheres (Liu et  al., 2011), and nanofibrous
spongy microspheres (Kuang et  al., 2015; Zhang et  al.,
2015b). Nanofibrous surface architecture is driven by the
same TIPS process described earlier, and microlevel archi-
tectures are determined by emulsion conditions. Nanofi-
brous hollow microspheres (NF-MSs) are fabricated from
star-shaped PLLA dendrimers dissolved in THF; glycerol
is slowly added to the emulsion before quenching in liquid
nitrogen to induce TIPS. NF-MSs are used as an injectable
platform for cartilage regeneration to successfully repair a
critical size osteochondral defect in rabbits, performing bet-
ter than commercially available poly(ethylene glycol) hydro-
gels (Liu et  al., 2011). Nanofibrous spongy microspheres
(NF-SMSs) are made similarly, beginning from star-shaped
PLLA, critical for a hollow microsphere architecture by act-
ing as a surfactant. A reverse emulsification process is imple-
mented where the THF/polymer solution is added into
glycerol, then quenched by liquid nitrogen to induce nano-
fiber formation (Kuang et  al., 2015; Zhang et  al., 2015b)
(Fig. 1.4.7.10). The combination of nanofibers and inter-
connected micropores is the result of a self-assembly process,
controlled by the number of arms in the core dendrimer and
arm length (Zhang et al., 2015b). The microporous struc-
ture maximizes cell–matrix interactions, in turn maximiz-
ing regenerative outcomes; NF-SMSs are shown to support
odontogenic differentiation of human dental pulp stem cells
and are a suitable injectable cell carrier for dentin regenera-
tion (Kuang et al., 2016). Injectable cell carriers have dem-
onstrated a great capacity for regeneration and interest in the
field. Future clinically motivated research in this area will
focus on how these carriers can be further tailored and modi-
fied to direct cell differentiation and be produced in mass.
 Surface Modification of Biomaterial
Constructs
Nanofibrous and porous materials have been explored for
their very high surface area to impart additional biologic
functionality. Cell–matrix interactions and cell fate can be
further modulated by providing additional cues that influ-
ence growth, adhesion, proliferation, and differentiation
(Ma, 2004). Early examples of scaffold modification are
direct modifications of scaffold surfaces to enhance the cell–
material interaction. Noncovalent deposition of biomacro-
molecules, including albumin, heparin, and RGD peptides,
to improve or resist surface adhesion (Ratner, 1993; Amiji
and Park, 1993). Plasma treatment has similarly been used
to promote protein immobilization (Nitschke, 2008). Spe-
cific to bone tissue engineering, hydroxyapatite surface coat-
ings have been used to promote bone formation and mineral
deposition by providing a site for mineral nucleation (Chen
et  al., 2006a; Zhang and Ma, 1999a, 2004; Ma et  al.,
2001). Mineral can also be deposited by mineral growth
CHAPTER 1.4.7   Textured and Porous Biomaterials 615
under an electric field, which helps to maintain small-scale
architectures of scaffolds (He et  al., 2010). Electrodeposi-
tion methods have also been developed to deposit charged
biomacromolecules to the surface of scaffolds in a layer-by-
layer method (Liu et  al., 2005; Zhu et  al., 2003). Other
growth factors and small proteins are commonly coated to
the surface of biomaterials to improve biologic outcomes;
recent advances in phage selection and genetic engineering
technologies are useful in determining application-specific
surface proteins to mediate biologic outcomes (Ramaraju
et al., 2017).
Chemically reactive functional groups can be incorpo-
rated into otherwise unreactive poly(aliphatic ester) chains
through copolymerization, allowing for more flexible mate-
rial design, which is amenable to modification (Shin et al.,
2003; Quirk et al., 2001). Barrera et al. demonstrated the
utility of poly(l-lactide)-co-poly(lysine) to attach RGD
peptides to terminal lysine residues and enhance cell adhe-
sion (Barrera et al., 1993). In the tin(II) 2-ethylhexanoate
(Sn(Oct)2)-catalyzed ring opening polymerization of l-lac-
tide, initiators can be chosen to impart end-group function-
ality, for example, hydroxy(alkyl)methacrylate (Zhang et al.,
2015a; Liu and Ma, 2010). Similarly, graft copolymers such
as poly(hydroxyalkyl(meth)acrylate)-g-poly(l-lactic acid)
contain repeating functional hydroxyl groups that can be
functionalized with bioactive molecules to control cell–
matrix interactions (Liu and Ma, 2010).
Finally, the high surface area of porous structures can be
used to incorporate biomolecule delivery systems. PLGA
nano- and microspheres are excellent candidates for encap-
sulation (Langer, 1998; Wei et  al., 2004), which can be
physically attached to the tissue-engineering construct by
solvent wetting throughout a 3D construct (Wei et  al.,
2007; Hu et al., 2009; Zhang et al., 2015a). More complex
delivery systems, for example, micro-RNA (Zhang et  al.,
2016a) and plasmid-DNA (Feng et al., 2017) delivery vec-
tors, are incorporated through two-stage delivery systems.
Growing interest in biologically derived therapeutics will
require new innovation to incorporate these deliverables
into adequate delivery and tissue-engineering systems. Mul-
tifunctional tissue-engineering scaffolds will be a large area
of exploration in the coming years. 
Summary and Future Perspectives
Textured and porous biomaterials show enhanced perfor-
mance in terms of both short- and long-term successes of
many biomedical devices by promoting cell adhesion, tissue
infiltration, host integration, and improved biocompatibility.
A high degree of fabrication controls over design architectures
at both micro- and nanoscales is paramount to the diverse
applications of biomaterials in clinically adopted medical
products. For example, texture is important at the nanoscale
to recapitulate the surface morphology of the native ECM-
mimicking proteins (collagen, elastin), which supports
cells and tissue organization, and porosity is important at
the microscale where highly interconnected pores support
616 SEC T I O N 1 . 4     Materials Processing

• Figure 1.4.7.10  Scanning electron microscopy images of nanofibrous spongy microspheres (A, D), nano-
fibrous microspheres (B, E), and smooth microsphere (C, F) with diameters ranging from 30 to 60 μm, for
use as injectable cell carriers (scale = 20 μm). hDPSCs attach to all three types of microspheres (D–F) after
24 h. Nanofibrous spongy microspheres are advantageous because of their increased porosity, which
allows for cell attachment on both the inside and outside of the cell (D, G). After just 12 h this is evident by
DNA quantification (G, #: P < .05, NF-SMS vs. S-MS, Δ: P < .05, NF-MS vs. S-MS). Subcutaneous injection
of hDPSC–microsphere complexes generated tissue after 4 weeks in vivo; solid triangles indicate micro-
spheres and hollow triangles indicate blood vessel formation. The most neotissue was formed with the
highly porous NF-SMS (H–J, scale = 50 μm). hDPSCs, Human dental pulp stem cells; NF-MS, nanofibrous
microspheres; NF-SMS, nanofibrous spongy microspheres; S-MS, solid microspheres. (Modified from
Kuang, R., Zhang, Z., Jin, X., Hu, J., Shi, S., Ni, L., Ma, P.X., 2016. Nanofibrous spongy microspheres for
the delivery of hypoxia-primed human dental pulp stem cells to regenerate vascularized dental pulp. Acta
Biomater. 33, 225–234.)

nutrient transfer, and promote cell migration and prolifera-
tion, leading to host integration. Both nanofibrous texture
and porosity increase construct surface area, creating space for
cells to attach and proliferate, and a space to embed other sig-
nals at the surface of polymeric constructs. Such biomaterial
architectural features can be achieved by using different fabri-
cation methods discussed in this chapter. Moreover, multiple
fabrication methods can be combined to fabricate constructs
with multiple levels of architectural features.
In the coming years significant expansion in the fields of
biomaterials science is expected, particularly in the areas of
regenerative medicine and tissue engineering. Some future
foreseeable challenges for porous and textured biomaterials are:
• Scalable processing: Many of the methods mentioned
in this chapter have been developed in academic set-
tings and are laborious in nature, making their scalabil-
ity potentially challenging for future industry partners.
Additionally, some steps in these processes, including
solvent evaporation, are not rapid and may require days
to weeks. In developing new biomaterial technologies,
scalability must be considered early in development to
facilitate future clinical and industry adoption.
• Advances in 3D printing: Macro-scale architectural
control of construct shape is conveniently accomplished
through 3D printing, and recently resolution has improved
dramatically (Chia and Wu, 2014). Means of combining
existing and new nano- and microscale feature fabrication
strategies with 3D printing remains a challenge.
• Range of biomaterial choices: A long-standing issue
with all biomaterial constructs is the limited selec-
tion of materials approved by the US Food and Drug
Administration for use in humans. Materials scientists
and engineers must find practical ways to maximize the
functionality and bioeffectiveness of approved materials.
• Compromised mechanical properties: Porous materi-
als inherently have a much higher surface area, directly
responsible for cell–material interfacial interactions, at the
expense of low density (Rouquerol et al., 1994; Sarkisov,
2012). Altered mechanical properties of materials as a
result of processing make it difficult to match those of the
surrounding tissues. Mismatch leads to insufficient inte-
gration capacity, and ultimately compromises longevity
and utility of biomaterial constructs. This mismatch can
lead to stress shielding, reduced interfacial stability, and
ultimately rejection by the host.
• Host reaction and long-term biosafety: Biomaterial
constructs must be strategically designed to synergize
with local tissues, rather than cause local inflammation,
which leads to rejection. Rather than fibrous tissue encap-
sulation, engineers must design biomaterial constructs
that interface with native tissue. Over the last 30 years,
the field of biomaterials has seen explosive growth, in
particular in novel processing technologies discussed in
this chapter, which increase biocompatibility and facili-
tate quicker, better outcomes for patients. Long-term
validation of the effects of these biomaterial implants and
products is still being assessed, and will inform future
CHAPTER 1.4.7   Textured and Porous Biomaterials 617
directions of the field. Biocompatibility studies, complete
with organ pathology studies, are necessary to demon-
strate the absence of systemic toxicity. Poly(l-lactide),
one of the most common synthetic biomaterials, has been
demonstrated safe beyond 110 weeks of in vivo implan-
tation (Pistner et  al., 1993). The effects of processing
techniques must be minimal to maintain the safety and
biocompatibility of such materials.
Despite these challenges, the biomaterial market
worldwide continues to expand at a rapid pace, valued at
US$134.3 billion in 2017, and will be a fruitful space for
innovation in processing, fabrication, and manufacturing
technologies (Rohan, 2017).
Increasing collaboration between clinicians, engineers,
and biologists will continue to move the field toward clini-
cal solutions. Recent trends in tissue engineering indicate
a movement toward cell-free therapies to avoid issues
with cell transplantation (Ikehara, 2013; Wei et al., 2007;
Zhang et  al., 2016a); tissue engineering constructs and
biomedical devices require increasingly more inherent bio-
instructive features to fill complex roles within physiologic
systems. Therefore continued development of fabrication
methods that allow for separate feature control at multiple
architectural levels will increase the tunability of scaffolds.
In developing new fabrication strategies, engineers and sci-
entists in the space of biomedical innovation must keep in
mind certain factors, including cost, fabrication simplicity,
batch-to-batch consistency, relevant mechanical properties,
biodegradability, and immune inertness. Additional work
to elucidate cellular mechanisms influencing cell–artificial
matrix interactions and long-term tissue-engineered con-
struct success is necessary, with appropriate controls. In
the coming years, biomaterials technology will continue
to expand and be refined to suit an even wider variety of
clinical needs.
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Chapter Exercises
1. What are the major challenges for successful structural
and functional integration of biomedical implants with
native tissues?
There is a clear need for seamless and functional inte-
gration of synthetic implants with host tissue. Proper-
ties of biomedical implants must be balanced with their
specific application. Important considerations include
vascularization and innervation, and minimizing fibrous
tissue encapsulation. Architectural and biochemical
properties of the cell microenvironment, particularly at
the cell–material interface, are critically important and
tailorable. For example, nanofibers promote cell adhe-
sion, proliferation, and differentiation on the material
surface; porous implants facilitate tissue ingrowth and
host integration.
2. Many strategies to engineer a functional tissue equiva-
lent propose the use of an appropriate biomaterial that mim-
ics the native ECM. What are the critical considerations of a
biomaterial to be considered appropriate?
Key considerations include recapitulating native mechan-
ical properties, physiological response, degradation rate and
degradation products, cell infiltration and integration, cost,
ease of manufacturing, and minimizing immune response.
These factors can be modulated by selecting materials with
appropriate mechanical properties, chemical composition
and degradation rates, surface modification, and choosing
appropriate fabrication methods for nano-, micro-, and
macrolevel architectures.
3. Collagen, in the native ECM, imparts tensile strength
to tissues. What aspects of collagen are structurally favorable?
How can this favorable 3D structure–function relationship
be recapitulated by synthetic biomaterials? What are the
limitations of naturally isolated collagen as a biomaterial?
Type I collagen, which composes a majority of the native
ECM, is a protein with a triple-helical fiber structure. Fiber
diameters are roughly 50–500 μm. Therefore synthetic
polymers must be fabricated with similar fiber diameters.
This is best accomplished by TIPS. Collagen lacks process-
ing control in regards to mechanical properties, degradation
rate, batch-to-batch inconsistencies, and pathogenicity.
4. You have synthesized a new biodegradable polymer
for potential use in tissue-engineering scaffold applications.
What design criteria would be implicated in:
a. Increasing cell adhesion to the scaffold construct? Nano-
fibrous surface texture.
b. Directing cell alignment in the scaffold construct?
Aligned macropores using a tubular porogen.
c. Promote osteogenic differentiation and calcium secre-
tion? Use the increased surface area of a nanofibrous
macroporous scaffold to adhere osteogenic factors such
as bone morphogenetic proteins or hydroxyapatite.
5. Angiogenesis is critical to influence tissue neogenesis
and integration of synthetic biomaterial constructs. What
strategies would you employ to enhance vascularization in a
synthetic prosthetic implant? Outline an appropriate exper-
iment, with controls, to test this strategy.
To enhance vascularization, blood vessels must be able
to form at the surface of and into the implanted construct.
Therefore a macroporous texture is advantageous to allow
cell and blood vessel infiltration. To test this hypothesis,
smooth and macroporous implants could be implanted into
an animal; after adequate time, histology for blood vessel
formation can be quantified.
6. A patient presents with a critical size osteochondral
defect (bone and cartilage) in their knee as the result of
repeated athletic injury. Describe a method for fabricating
a tissue-engineering scaffold that is suitable for regeneration
of both tissue types in this defect.
Bone and cartilage must be combined in the same tis-
sue-engineering construct in two distinct regions. Consid-
erations may include pore size, pore interconnectivity, and
surface decoration.
7. You are a senior staff scientist at a pharmaceutical
company, working in the biomedical devices and implants
division. The director of research and development has
tasked you with leading a phase 1 project of an implantable
biosensor for optical blood pressure sensing. What specific
features would you propose to increase biocompatibility of
the synthetic construct?
To increase long-term device success, you want it to inte-
grate with the surrounding tissue without being encapsu-
lated by fibrous tissue. Therefore ECM-like nanofibers and/
or a porous surface texture are important to allow tissue
ingrowth.
8. Implantation of biomaterials leads to a host of reac-
tions that can be characterized by a series of cellular
responses. You are tasked with designing a composite tem-
poral mandibular joint implant. In general, how would you
circumvent complications associated with host rejection
and expedite wound healing?
ECM-like nanofibers and/or a porous surface texture are
important to allow tissue ingrowth. Pores, in particular, are
advantageous and must be large enough to facilitate cell and
tissue infiltration, but small enough to prevent fibrous tis-
sue formation. Nanofibers are important to disrupt capsule
formation by disrupting collagen fiber orientation.
622.e1