jurnal

Critical Reviews in Therapeutic Drug Carrier Systems, 29(1), 163 (2012)

0743-4863/12/$35.00 2012 Begell House, Inc. www.begellhouse.com 1

Scaffold: A Novel Carrier for Cell and Drug DeliveryTarun Garg,* Onkar Singh, Saahil Arora & R.S.R. Murthy

Department of Pharmaceutics, ISF College of Pharmacy, Moga (Punjab), India 09501223252(M)

*Address all correspondence to: Tarun Garg; Tel.: 09829752244; [email protected].

ABSTRACT: Scaffolds are implants or injects, which are used to deliver cells, drugs, and genes into the body. Different forms of polymeric scaffolds for cell/drug delivery are avail-able: (1) a typical three-dimensional porous matrix, (2) a nanofibrous matrix, (3) a thermosen-sitive sol-gel transition hydrogel, and (4) a porous microsphere. A scaffold provides a suitable substrate for cell attachment, cell proliferation, differentiated function, and cell migration. Scaffold matrices can be used to achieve drug delivery with high loading and efficiency to specific sites. Biomaterials used for fabrication of scaffold may be natural polymers such as alginate, proteins, collagens, gelatin, fibrins, and albumin, or synthetic polymers such as polyvinyl alcohol and polyglycolide. Bioceramics such as hydroxyapatites and tricalcium phosphates also are used. Techniques used for fabrication of a scaffold include particulate leaching, freeze-drying, supercritical fluid technology, thermally induced phase separation, rapid prototyping, powder compaction, sol-gel, and melt moulding. These techniques allow the preparation of porous structures with regular porosity. Scaffold are used successfully in various fields of tissue engineering such as bone formation, periodontal regeneration, repair of nasal and auricular malformations, cartilage development, as artificial corneas, as heart valves, in tendon repair ,in ligament replacement, and in tumors. They also are used in joint pain inflammation, diabetes, heart disease, osteochondrogenesis, and wound dressings. Their application of late has extended to delivery of drugs and genetic materials, including plasmid DNA, at a controlled rate over a long period of time. In addition, the incorporation of drugs (i.e., inflammatory inhibitors and/or antibiotics) into scaffolds may be used to prevent infec-tion after surgery and other disease for longer duration. Scaffold also can be used to provide adequate signals (e.g., through the use of adhesion peptides and growth factors) to the cells, to induce and maintain them in their desired differentiation stage, and to maintain their survival and growth. The present review gives a detailed account of the need for the development of scaffolds along with the materials used and techniques adopted to manufacture scaffolds for tissue engineering and for prolonged drug delivery.

KEY WORDS: scaffold, tissue engineering, implants, prolonged drug delivery, tissue regen-eration, graft surgery

I. INTRODUCTION

Tissue engineering aims to replace or facilitate the regrowth of damaged or diseased tis-sue by applying a combination of biomaterials, cells and bioactive molecules.1 Every day thousands of clinical procedures are performed to replace or repair tissues in the human body that have been damaged through disease or trauma. The damaged tissue is replaced by using donor graft tissues (autografts, allografts, or xenografts), but the main problems

Critical Reviews in Therapeutic Drug Carrier Systems

2 Garg et al.

associated with this are a shortage of donors or donor sites, transmission of disease, rejec-tion of grafts, donor site pain and morbidity, the volume of donor tissue that can be safely harvested, and the possibility of harmful immune responses.2 Compared with replacing damaged tissues with grafts, tissue engineering, or regenerative medicine, there are aims to regenerate damaged tissues by developing biological substitutes that restore, maintain, or improve tissue function.3,4 In the last 2 decades, the research and development among the scientific community in this emerging field of tissue engineering and regenerative medicine has progressed at a rapid rate.5 Biodegradable polymeric scaffolds for tissue en-gineering have received much attention because they provide a temporal and spatial en-vironment for cellular growth and tissue in-growth.68 Scaffold is the central component that is used to deliver cells, drugs, and genes into the body. The definition of the scaffold is categorized into 2 main categories: (1) a cell delivery scaffold and (2) a drug deliv-ery scaffold. When cells are implanted or seeded into an artificial structure capable of supporting three-dimensional (3D) tissue formation, these structures typically are called cell delivery scaffolds, and when drugs are loaded into a 3D artificial porous structure capable of high drug loading efficiency and sustained release of a drug for longer dura-tion, they typically are called drug delivery scaffolds.9 Different forms of polymeric scaffolds for cell/drug delivery are available: (1) a typical 3D porous matrix, which is a highly porous and well interconnected open pore structure that allows high cell seed-ing density and tissue in-growth, as shown in (Fig. 1A); (2) a nanofibrous matrix that is prepared by electrospinning or self-assembly would provide a better resemblance of the physiological environment (Fig. 1B)8,10; (3) a thermosensitive sol-gel transition hydrogel (Fig. 1C); and (4) a porous microsphere (Fig. 1D). These are already widely utilized as sustained protein-release formulations and have been applied in tissue engineering for the potential use as a cell delivery carrier or supportive matrix.11,12

Of the polymeric scaffolds listed above, a typical 3D porous matrix and nanofibrous matrix are the implantable forms and a thermosensitive sol-gel transition hydrogel and

Figure 1. Different forms of polymeric scaffolds for cell/drug/gene delivery: three-dimensional porous matrix (A); nanofiber mesh (B); hydrogel (C); and microsphere (D).

Volume 29, Number 1, 2012

A Novel Carrier for Cell and Drug Delivery 3

porous microsphere are the injectable forms. Tissue engineering technologies are based on this biological triad and involve the successful interaction between three compo-nents: (1) the scaffold that holds the cells together to create the tissues physical form; (2) the cells that create the tissue; and (3) the biological signalling molecules, such as growth factors, that direct the cells to express the desired tissue phenotype (Fig. 2).13

Scaffold for tissue engineering (cell delivery) should posses the following:1. Mechanical properties that are sufficient to shield cells from tensile forces with-

out inhibiting biomechanical cues 2. Desired volume, shape, and mechanical strength8 3. Acceptable biocompatibility 4. A highly porous and well-interconnected open pore structure to allow high cell

seeding density and tissue in-growth5. Bioadsorption at predetermined time period 6. Biocompatible chemical compositions and their degradation products, causing

minimal immune or inflammatory responses14 7. Physical structure to support cell adhesion and proliferation, facilitating cell

cell contact and cell migration15 Scaffold for drug delivery should posses the following:1. Homogenous drug dispersion throughout the scaffold 2. Ability to release the drug at a predetermined rate 3. Drug binding affinity that is sufficiently low to allow the drug released to be stable

when incorporated in the scaffold at a physiological temperature 4. Stable physical dimension, chemical structure, and biological activity over a

prolonged period of time. There is a significant challenge in the design and manufacture of scaffolds that pos-

sess all of the above requirements and the ability to control the release kinetics of drug or growth factors over the period of treatment or tissue regeneration.9

Figure 2. The tissue engineering triad.


4 Garg et al.

II. PROPERTIES OF SCAFFOLD MATRICES IN CELL/DRUG DELIVERY

Scaffolds play a critical role in tissue engineering. The function of scaffolds is to direct the growth of cells either seeded within the porous structure of the scaffold or migrating from surrounding tissue. The majority of mammalian cell types are anchorage-depen-dent, meaning they will die if an adhesion substrate is not provided. Scaffold matri-ces can be used to achieve cell delivery with high loading and efficiency to specific sites. Therefore, the scaffold must provide a suitable substrate for cell attachment, cell proliferation, differentiated function, and cell migration1619 to permit the transport of nutrients, waste, and biological signalling factors to allow for cell survival. The ma-trix material should be biodegrade at a controllable rate that approximates the rate of natural tissue regeneration and should provoke a minimal immune and/or inflamma-tory response in vivo.13 Tissue engineering scaffolds are meant to be colonized by cells and should transmit the chemical and physical cues necessary to ensure adequate tissue growth. Synthetic polymer scaffolds may be used to deliver proteins and growth factors with or without cells locally to enhance tissue repair and regeneration.9 An ideal tissue engineering scaffold should fulfill the following 11 requirements.20

II.A. Biocompatibility

The scaffold should possess acceptable biocompatibility and toxicity profiles.16 Bio-compatibility is the ability of the scaffold to perform in a specific application without eliciting a harmful immune or inflammatory reaction.13 If the scaffold is nontoxic and degradable, new tissue will eventually replace it, whereas if it is nontoxic and biologi-cally active, the scaffold will integrate with the surrounding tissue. However, if the scaf-fold is biologically inactive, it may be encapsulated by a fibrous capsule; in the worst case, when the scaffold is toxic, rejection of the scaffold and localized death of the sur-rounding tissue can occur.21

II.B. Biodegradability

The scaffold material should be biodegradable. Its degradation products should not be toxic and should be eliminated easily from the implantation site by the body,13 eliminat-ing the need for further surgery to remove it.22 The scaffolds degradation rate should be adjusted to match the rate of tissue regeneration so that it has disappeared completely once the tissue is repaired.16

II.C. Mechanical Properties

Mechanical properties of the scaffold should match those of the tissue at the implanta-tion site, or the mechanical properties at least should be sufficient to shield cells from damaging compressive or tensile forces without inhibiting appropriate biomechanical cues15,23 and to survive under physiological conditions. Immediately after implantation,



the scaffold should provide a minimal level of biomechanical function that should im-prove progressively until normal tissue function has been restored, at which point the construct should have fully integrated with the surrounding host tissue.13

II.D. Structure

It should have a reproducible microscopic and macroscopic structure with a high surface:volume ratio suitable for cell/drug attachment.16

II.E. Interface Adherence

Interface adherence is how cells or proteins attach to a scaffolds surface. The scaffold should support cell adhesion and proliferation, facilitating cellcell contact and cell mi-gration.15

II.F. Porosity

Porous structures allow for optimal interaction of the scaffold with cells.13 Specifically, pore size determines the efficiency at which cells seed into the scaffold24; small pores prevent the cells from penetrating the scaffold, whilst large pores prevent cell attach-ment due to a reduced area and, therefore, available ligand density.13 The scaffold should have an adequate porosity; this includes the magnitude of the porosity, the pore size distribution, and its interconnectivity. This also will allow cell in-growth and vasculari-sation and promote metabolite transport.16 A scaffold with an open and interconnected pore network and a high degree of porosity (>90%) is ideal for the scaffold to interact and integrate with the host tissue.25

II. G. Nature

Mimicking the native extracellular matrix (ECM), an endogenous substance that sur-rounds cells, allows them to bind into tissues and provide signals that aid cellular devel-opment and morphogenesis.15,26

II.H. Processability

The scaffold should possess relatively easy processability and malleability into the de-sired shape, according to the need. They should be capable of being produced into a sterile product.

II.I. Loading Capacity Release Kinetics

Loading capacity release kinetics is defined as the amount of drug that can be mixed into the scaffold. The scaffold should have a maximum loading capacity so the drug is


6 Garg et al.

released continuously for longer duration after insertion into the body. The drug needs to be dispersed homogenously throughout the scaffold or in discrete areas and must avoid an initial burst effect. The drug release from the scaffold needs to be controlled to allow the appropriate dose of drug to reach the cells over a given period of time.

II.J. Binding Affinity

Binding affinity is defined as how tightly the drug binds the scaffold; this binding affin-ity must be sufficiently low to allow release of the drug; however, low binding affinity would lead to dose dumping, which eventually may produce toxic effects.

II.K. Stability

The stability of the incorporated drug/cell at physiological temperature with respect to physical, chemical, and biological activity is to be assessed. They should posses di-mensional stability, chemical stability, and biological activity over a prolonged period of time.9

III. DESIGN STRATEGIES FOR CELL AND DRUG DELIVERY SYSTEMS

Although prefabricated scaffolds are most widely used for tissue regeneration as well as drug delivery purposes, different forms of polymeric scaffolds for cell/drug delivery are also available. These forms can be classified as (1) a typical 3D porous matrix, (2) a nanofibrous matrix, (3) a thermosensitive sol-gel transition hydrogel, and (4) a porous microsphere. Of these, the typical 3D porous matrix and nanofibrous matrix are the implantable forms and the thermosensitive sol-gel transition hydrogel and the porous microsphere are the injectable forms. Injectable scaffold materials formed in situ have received much attention recently because they can be administered using a syringe needle15 and thus avoid surgery. To mimic the topological and microstructural characteristics of the ECM, a biomaterial must have a high degree of porosity, a high surface:volume ratio, a high degree of pore interconnection, appropriate pore size, and geometry control.27 These properties can be well controlled in an injectable scaffold. Some of the drug/cell delivery systems and their design strategies are given in the fol-lowing sections.

III.A. Hydrogel-Based Systems

Hydrogel matrices are physically or chemically cross-linked, water-soluble polymers, which swell to form a gel like substance on exposure to water.28 Hydrogels are appealing for biological applications because of their high water content and biocompatibility.29 Hydrogels can be made from naturally occurring polymers such as collagen, chitosan, and gelatine or synthetic polymers such as poly(ethylene glycolide) and poly vinyl alco-hol. Growth factors are released from hydrogels through diffusion of the growth factor



through the highly hydrophilic scaffold, mechanical stimulation, or hydrolytic degrada-tion of the scaffold28 or upon swelling in response to an environmental stimulus. For example, gelatin and dextran can be fabricated as an interpenetrating polymer hydrogel for drug delivery and can exhibit an intelligent property of degradation in response to dual stimuli.30 Release behavior can be regulated by controlling the chemical and physi-cal properties of the gels from a few days to several months.31 Above critical concentra-tions, these hydrogels show a sol state at room temperature, but change into a gel state at body temperature15; hydrogels can be administered in a minimally invasive manner and therefore they are used in tissue engineering strategies as a potential cell and protein delivery vehicle.27 Additional advantages of hydrogels are that they may protect drugs, peptides, and especially proteins against the potentially harsh environment in the vicin-ity of the release site; they enable enhanced residence times, sustained delivery, and/or targeted drug delivery29; and they have significant potential in wound healing applica-tions, though pore size and degradation properties must be optimized.27 For example, in-jectable poly(N-isopropylacrylamide) physical hydrogels encapsulating cells have been prepared for cartilage and nerve regeneration.32,33 Pluronic/heparin composite hydrogels delivering growth factor also have been studied to induce angiogenesis.34 Photo cross-linked poly(ethylene glycol) (PEG)based hydrogels have been utilized for delivery of chondrocytes and osteoblasts.3537 Bone morphogenic protein introduced into the hydro-gel material (temperature-sensitive chitosan-polyol salt combination) has been effective in promoting de novo bone and cartilage formation in vivo.38 Poly(lactic acidglycolic acid) (PLGA) grafted with PEG and PEG grafted with PLGA hydrogels capable of sus-tained insulin delivery and cartilage repair were synthesized.39 Pluronic copolymers at a higher concentration (more than 20% [w/v]) have been used to encapsulate chondro-cytes and produce engineered cartilage.40

III.B. Microsphere- and Microparticle-based Systems

Microspheres and microparticles have attracted attention as carrier matrices in both the biomedicine and bioengineering fields and could satisfy the need of delivering biomol-ecules such as growth factors, genes, and cells.41 Prior to injection, the porous structure (30 m) would allow sufficient cell seeding in and out of the matrix. After injection in vivo, the porous matrix would permit infiltration of cells and ingrowth of tissue from the host, facilitating the regeneration process.15 Microparticles also can be used as inject-able scaffolds to support cell growth and proliferation directly and as vehicles of growth factor, and to enhance cell proliferation and expansion simultaneously.27 Microsphere-based technology has an application for tissue engineering as well as gene therapy. Gene delivery has several potential advantages, such as the inherent stability of plasmid DNA, reduced fabrication costs, extended shelf-life, a more economical use , and application in skin repair.42 Application is pellets incorporated with basic fibroblast growth factorloaded microspheres into alginate porous scaffolds to enhance vascularization after im-plantation in the rat peritoneum. Chitosan scaffolds loaded with basic fibroblast growth factor contained in gelatin microparticles were effective in accelerating wound closure


8 Garg et al.

of pressure ulcers.43 Biodegradable PLGA microspheres have been studied for delivery of chondrocytes for cartilage engineering.15 Nanofabricated particles could offer better delivery properties to direct cell fate and to regulate processes such an angiogenesis and cell migration.27

III.C. Membrane-based Systems

Human skin is considered the gold standard for treatment of skin wounds. However, skin grafts are not always the perfect solution. They are limited in terms of the conditions needed for tissue availability, graft rejections, and conformability with the surround-ing tissue with respect to thickness and pigmentation.44,45 Current strategies for wound dressings have been aimed at the development of the bilayer-structured membrane, with incorporation of growth factors into these matrices for improved healing. For example, gelatin hydrogel containing epidermal growth factorloaded microspheres has an en-hanced effect on re-epithelization, improving the healing of the wound area. Antibiotics should be incorporated into the membranes to prevent infections because sustaining a sufficient drug concentration at the site of infection is important for the treatment of an infected wound. For example, a bilayered membrane combines silver sulphadiazine and a laminin-modified collagen membrane, which was shown to facilitate the dermal wound healing process.46

IV. BIOMATERIALS FOR SCAFFOLD FABRICATION

A number of different categories of biomaterials are commonly used as scaffold for cell and drug delivery.

IV.A. Natural Polymers

Natural polymers include alginate, proteins, collagens, gelatin, fibrins, albumin, elsinan, pectin (pectinic acid), galactan, curdlan, gellan, levan, emulsan, dextran, pullulan, gluten, elastin, fibroin, hyarulonic acid, cellulose, starch, chitosan (chitin), scleroglucan, heparin, silk, chondroitin 6-sulfate, and polyhydroxyalkanoates. They can be used as biomateri-als for cell/drug/gene delivery purposes. Advantages of natural polymers include their biocompatibility, commercial availability, easy processing, and they more closely mimic the natural ECM of tissues; however, limitations are short supply, expense, batch-to-batch variation, and susceptibility to cross-contamination.47 Different natural polymers and their properties, advantages, disadvantages, and applications are described in Table 1.

IV.B. Synthetic Polymers

Synthetic polymers are largely divided into two categories: biodegradable and nonbio-degradeable. Biodegradable polymers are polyglycolide, polylactide and its copolymer poly(lactide-co-glycolide), polyphosphazene, polyanhydride, poly(propylene fuma-



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ndan

t R

enew

able

Inex

pens

ive

Env

ironm

ent f

riend

ly B

iode

-gr

adea

ble

App

licat

ion

of s

oy-b

ased

po

lym

ers

in th

is fi

eld

is s

till v

ery

narr

ow

Gro

wth

fact

or,

cell

and

drug

del

iver

y, in

the

food

in

dust

ry, c

ompu

ter c

asin

gs,

elec

troni

c ch

ip p

acka

ging

TAb

le 1

. (co

ntin

ued)



Scaf

fold

N

o.Po

lym

ers

and

Prop

ertie

s

Adv

anta

ges

Dis

adva

ntag

esA

pplic

atio

ns

A.2

.A

.2.1

Poly

sacc

harid

e po

lym

ers

Chi

tosa

n57,

58,7

678

A fu

lly/p

artia

lly d

eace

ty-

late

d fo

rm o

f chi

tin. D

egre

e of

de

acet

ylat

ion

of c

omm

erci

al

chito

san

is u

sual

ly b

etw

een

70%

and

95%

, and

the

mo-

lecu

lar w

eigh

t bet

wee

n 10

and

10

00 k

Da.

Chi

tosa

n ex

hibi

ts

a pH

-sen

sitiv

e be

havi

or a

s a

wea

k po

ly-b

ase

beca

use

of

the

larg

e qu

antit

ies

of a

min

o gr

oups

on

its c

hain

.

Bio

logi

cally

rene

wab

leB

iode

grad

able

and

bio

com

-pa

tible

Non

antig

enic

and

non

toxi

cB

iofu

nctio

nal

Inex

pens

ive

Add

ition

al c

ontro

l ove

r chi

to-

san

s fin

al p

rope

rty

Indu

ces

rapi

d bo

ne re

gene

ra-

tion

at in

itial

sta

ges

Bon

e fo

rmat

ion

afte

r im

plan

ting

thes

e m

atric

es o

ccur

s ov

er a

lo

ng p

erio

d (s

ever

al m

onth

s or

ye

ars)

.

Bon

e an

d ca

rtila

ge, n

erve

, sk

in,

perio

dont

al b

one,

os

teoc

hond

ral,

vasc

ular

iza-

tion,

wou

nd d

ress

ing,

dr

ug d

eliv

ery,

enc

apsu

la-

tion

of c

ells

, sut

ures

A.2

.2St

arch

57,7

981

Sta

rch

is s

tore

d as

inso

lubl

e gr

anul

es c

ompo

sed

of

am

y-la

se (2

030

%) a

nd a

myl

opec

-tin

(70

80%

).P

hysi

cal p

rope

rties

of s

tarc

h ar

e gr

eatly

influ

ence

d by

the

amou

nt o

f wat

er p

rese

nt.

Deg

rada

tion

prod

ucts

are

ol

igo

sacc

harid

es th

at c

an

be re

adily

met

abol

ized

to

prod

uce

ener

gy.

Inhe

rent

bio

degr

adab

-ility

O

verw

helm

ing

Abu

ndan

ce

Ren

ewab

ility

Ext

rem

ely

diffi

cult

to p

roce

ss

Brit

tle

Sem

icry

stal

line

nativ

e st

arch

gr

anul

es s

truct

ure

is e

ither

de-

stro

yed,

reor

gani

zed,

or b

oth.

Bon

e, v

ascu

lariz

atio

n, d

rug

deliv

ery

incl

udin

g ca

ncer

th

erap

y, n

asal

adm

inis

tra-

tion

of in

sulin

A.2

.3A

lgin

ate1

3,57

,58,

82

Orig

inat

es fr

om s

eaw

eed

and

is s

truct

ural

ly s

imila

r to

natu

ral

GA

Gs.

It is

an

anio

nic

poly

mer

w

ith c

arbo

xyl e

nd g

roup

s is

a

good

muc

oadh

esiv

e ag

ent

with

a h

igh

degr

ee o

f sw

ellin

g an

d sh

rinki

ng d

urin

g ca

tioni

c cr

oss-

link

ing.

Bio

com

patib

le

Sim

ple

gela

tion

met

hods

Res

ista

nce

to a

cid

cond

ition

Poo

r mec

hani

cal p

rope

rties

U

ncon

trolle

d de

grad

atio

n ki

net-

ics

Dru

g lo

ss b

y le

achi

ng

Bon

e an

d ca

rtila

ge, v

as-

cula

rizat

ion,

inte

rver

tebr

al

disc

, liv

er a

nd p

ancr

eas,

drug

del

iver

y, e

ncap

sula

-tio

n of

cel

ls, s

utur

es,

wou

nd d

ress

ings

, per

iph-

eral

ner

ve re

gene

ratio

n,ge

ne e

xpre

ssio

n

TAb

le 1

. (co

ntin

ued)


12 Garg et al.

Scaf

fold

N

o.Po

lym

ers

and

Prop

ertie

s

Adv

anta

ges

Dis

adva

ntag

esA

pplic

atio

ns

A.2

.4H

yalu

roni

c ac

id57

,58,

838

8

This

is a

maj

or m

acro

mol

ecu-

lar c

ompo

nent

of t

he E

CM

.H

yalu

rona

n is

a n

atur

ally

oc-

curr

ing,

non

sulfa

ted

glyc

os-

amin

o-gl

ycan

and

a m

ajor

m

acro

mol

ecul

ar c

ompo

nent

of

the

inte

r-ce

llula

r mat

rix o

f m

ost c

onne

ctiv

e tis

sues

suc

h as

car

tilag

e, v

itreo

us o

f hu-

man

eye

, um

bilic

al c

ord,

and

sy

novi

al fl

uid.

Bio

com

patib

leE

asily

func

tiona

lized

Goo

d ce

ll re

cogn

ition

Eas

ily a

nd c

ontro

llabl

y pr

o-du

ced

in a

larg

e sc

ale

thro

ugh

mic

robi

al fe

rmen

tatio

n

Poo

r mec

hani

cal p

rope

rties

E

xpen

se o

f pre

serv

atio

n an

d st

orag

e in

a c

ryo-

freez

er.

Adi

pose

, car

tilag

e, b

one,

ne

rves

, ski

n, v

ascu

lariz

a-tio

n, s

pina

l cor

d, o

steo

-ch

ondr

al, d

rug

deliv

ery,

de

rmal

, nas

al, p

ulm

onar

y,

lipos

ome

mod

ified

, im

plan

t-ab

le d

eliv

ery

devi

ces

for

gene

del

iver

y, d

rug

targ

et-

ing,

cho

ndro

gene

sis

A.2

.5C

hond

roiti

n su

lpha

te57

,89,

90

This

is th

e m

ost p

hysi

olog

i-ca

lly im

porta

nt G

AG

s.B

ioch

arac

teris

tics

of G

AG

s in

clud

e th

e bi

ndin

g an

d m

odul

atio

n of

gro

wth

fact

ors

and

cyto

kine

s, th

e in

hibi

tion

of p

rote

ases

, and

the

invo

lve-

men

t in

adhe

sion

, mig

ratio

n,

prol

ifera

tion,

and

diff

eren

tia-

tion

of c

ells

.

Non

imm

unog

enic

Deg

rade

s to

non

toxi

c ol

igo-

sacc

harid

esS

hock

abs

orbe

r

Rea

dily

wat

er-s

olub

le n

atur

e A

pplic

atio

n as

a s

olid

-sta

te d

rug

deliv

ery

vehi

cle

It is

usu

al to

car

ry o

ut a

cro

ss-

linki

ng tr

eatm

ent w

ith p

olym

ers,

su

ch a

s ch

itosa

n, g

elat

in, c

ol-

lage

n, h

yalu

rona

n, p

oly(

viny

l al

coho

l), to

pro

duce

mor

e st

able

m

ater

ials

.

Car

tilag

e an

d bo

ne, v

as-

cula

rizat

ion,

hea

rt va

lve,

ki

dney

, dru

g de

liver

y,

cent

ral n

ervo

us s

yste

m,

skin

A.2

.6D

extr

an57

,91

93

Dex

tran

is a

bra

nche

d, h

igh

mol

ecul

ar w

eigh

t pol

ymer

of

D-g

luco

se, p

rodu

ced

by

diffe

rent

bac

teria

l stra

ins

by

dext

rans

ucra

se e

nzym

efro

m s

ucro

se.

Bio

degr

adab

le a

nd b

ioco

m-

patib

leR

educ

es a

ggre

gatio

n an

d ad

hesi

vene

ssR

eadi

ly a

vaila

ble

in a

wid

e ra

nge

of m

olec

ular

wei

ghts

al

ong

with

sev

eral

der

ivat

ives

Cos

t O

ver h

ydra

tion

Ana

phyl

axis

R

isks

of c

oagu

latio

nab

norm

aliti

es

Bon

e, b

lood

sub

stitu

tes,

plas

ma

expa

nder

s,

drug

del

iver

y, g

uide

d ce

ll an

d ax

onal

rege

nera

tion,

ca

rtila

ge ti

ssue

eng

inee

ring

TAb

le 1

. (co

ntin

ued)



Scaf

fold

N

o.Po

lym

ers

and

Prop

ertie

s

Adv

anta

ges

Dis

adva

ntag

esA

pplic

atio

ns

A.2

.7A

gar5

7,58

,94,

95

Aga

r for

ms

ther

mor

ever

s-ib

le g

els

diss

olve

d in

wat

er.

The

visc

oela

stic

pro

perti

es o

f ag

aros

e ge

ls d

ecre

ase

with

a

decr

ease

in th

e de

gree

of d

e-su

lfatio

n of

its

nativ

e po

lysa

c-ch

arid

e ag

ar.

Bio

com

patib

leB

iode

grad

eabl

eD

ifficu

lt to

pro

cess

Diffi

cult

to o

btai

n fro

m re

sour

c-es

Car

tilag

e an

d bo

ne,

hear

t, ne

rve,

pan

crea

s,in

terv

erte

bral

dis

c, c

orne

a,

wou

nds

A.2.

8C

arra

geen

ans9

610

1

Extra

cted

from

red

mar

ine

al-

gae,

can

form

a th

erm

orev

ers-

ible

gel

at r

oom

tem

pera

ture

. D

ue to

the

stro

ng io

nic

natu

re,

carra

geen

ans

exhi

bit a

hig

h de

gree

of p

rote

in re

activ

ity.

Thix

otro

pic

natu

re H

ighl

y fle

x-ib

lem

olec

ules

Hig

h m

eltin

g te

mpe

ra-tu

reW

hen

a ge

l-ind

ucin

g re

agen

t is

not

pre

sent

in th

e re

actio

n m

ixtu

re, d

isso

lutio

n of

the

gel w

ill oc

cur

Dru

g de

liver

y,in

the

food

indu

stry

,bo

ne ti

ssue

eng

inee

ring

A.2.

9G

ella

n gu

m57

,92

This

is p

rodu

ced

byPs

eudo

mon

as e

lode

a. It

s ab

le

to fo

rm tr

ansp

aren

t gel

s, in

its

nativ

e or

hig

h ac

yl fo

rm, a

nd

two

acyl

sub

stitu

ents

D-a

ceta

te

and

D-g

lyce

rate

are

pre

sent

Res

ista

nt to

hea

t and

aci

dTh

e hi

gh a

cyl f

orm

pro

duce

s tra

nspa

rent

, sof

t, el

astic

, and

fle

xibl

e ge

ls

Low

acy

l for

m p

rodu

ces

firm

, no

nela

stic

brit

tle

Food

indu

stry

, dru

g de

-liv

ery,

oph

thal

mol

ogy,

as

adju

vant

s an

d as

veh

icle

s fo

r dru

g de

liver

y

A2.

10C

ellu

lose

57,1

021

04

Cel

lulo

se is

the

mos

t abu

n-da

nt o

rgan

ic p

olym

er in

the

wor

ld. I

ts h

ighl

y co

hesi

ve,

hydr

ogen

-bon

ded

stru

ctur

e gi

ves

cellu

lose

fibe

rs e

xcep

-tio

nal s

treng

th a

nd m

akes

th

em w

ater

inso

lubl

e de

spite

thei

r hyd

ro-

phili

city

.

Rea

dily

ava

ilabl

e Lo

w c

ost

Eas

ily c

onve

rted

into

der

iva-

tives

S

tabi

lizes

the

stru

ctur

e P

orou

s B

ioco

mpa

tible

Poo

r deg

rada

tion

in v

ivo

Nee

ds m

ore

time

to re

gene

rate

Car

tilag

e an

d bo

ne,

card

iac,

adh

esio

n ba

rrie

r, he

mos

tat,

cell

cultu

re

TAb

le 1

. (co

ntin

ued)


14 Garg et al.

Scaf

fold

N

o.Po

lym

ers

and

Prop

ertie

s

Adv

anta

ges

Dis

adva

ntag

esA

pplic

atio

ns

A2.

11G

alac

tose

105

Gal

acto

se is

reco

gniz

ed b

y m

amm

alia

n he

pato

cyte

s th

roug

h an

asi

alog

lyco

prot

ein

rece

ptor

lead

ing

to re

gula

tion

of a

deg

rada

tive

path

way

in

glyc

opro

tein

hom

eost

asis

.

Impr

oved

cel

l atta

ch-m

ent,

viab

ility

, and

met

abol

ic fu

nc-

tions

Less

sta

ble

Live

r, bo

ne, c

artil

age

A2.

12H

epar

in15

Hep

arin

is a

hig

hly

sulfa

ted

GA

G c

onst

itutin

g th

e E

CM

Hep

arin

bin

ding

pre

serv

e th

e st

abili

ty a

nd b

iolo

gica

l act

ivity

of

the

grow

th fa

ctor

s

Whe

n ce

lls a

re im

bibe

d in

this

sc

affo

ld, t

he re

quire

a lo

nger

du

ratio

n fo

rgr

owth

Sus

tain

ed re

leas

e of

gr

owth

fact

ors,

bone

,ca

rtila

geE

CM

, ext

race

llula

r mat

rix; G

AG

, gly

cosa

min

ogly

cans

.

TAb

le 1

. (co

ntin

ued)



rate), polycyanoacrylate, polycaprolactone, polydioxanone, and polyurethanes. Non-biodegradeable polymers include polyvinyl alcohol, polyhydroxyethymethacrylate, and poly(N-isopropylacrylamide). Advantages of this scaffold are easily controlled physi-cochemical properties and quality, no immunogenicity, processing with various tech-niques, and consistent supply of large quantities.13 Different synthetic polymers and their properties, advantages, disadvantages, and applications are described in Table 2.

IV.C. Bioceramics

Melting inorganic raw materials to create an amorphous or crystalline solid body is known as bioceramics, and these porous final products are used mainly for scaffolds. Bioceramics classified as (1) nonresorbable (relatively inert), for example alumina, zir-conia, and silicon nitride; and (2) bioactive or surface active (semi-inert), for example glass ceramics such as dense hydroxyapatites [9CaOCa (OH)23P2O5], and biodegrad-able or resorbable (noninert) such as calcium phosphates, aluminium calcium phos-phates, coralline, tricalcium phosphates (3CaOP2O5), zinc calcium phosphorus oxides, zinc sulphate calcium phosphates, ferric calcium phosphorus oxides, and calcium alu-minates.13 Bioceramics polymers and their properties, advantages, disadvantages, and applications are described in Table 3.

IV.D. Composites

Because of some of the problems associated with using scaffolds synthesised from a single-phase biomaterial (poor mechanical properties and biocompatibility of natural and synthetic polymers and poor degradability of bioceramics), a number of research-ers have developed composite scaffolds comprising two or more phases to combine the advantageous properties of each phase. Combinations of (1) syntheticsynthetic, (2) syntheticnatural and (3) naturalnatural polymers have ability to tailor mechanical, degradation, and biological properties but compromise the best qualities of individual polymers with properties of the overall scaffold.13 Composite polymers and their proper-ties, advantages, disadvantages, and applications are described in Table 4.

V. SCAFFOLD FABRICATION TECHNIQUES

In the body, cells and tissue are organized into 3D architecture. To engineer these func-tional tissue and organs, scaffolds have to be fabricated by different methodologies to facilitate the cell distribution and guide their growth into 3D space. The conventional methods include fiber mesh, fiber bonding, melt molding, solvent casting/particulate leaching, gas foaming/particulate leaching, phase separation, and high-pressure process-ing. Electrospinning also has been utilized in producing a nanofibrous 3D matrix, and rapid prototyping technologies have enabled solid free-form fabrication directly from a computer-aided design (CAD) model.15 Many different techniques that are used to fabri-cate scaffolds for tissue engineering are summarized in the following sections.


16 Garg et al.

Scaf

fold

N

o.Po

lym

ers

and

Prop

ertie

sA

dvan

tage

sD

isad

vant

ages

App

licat

ions

B.1

.B

.1.1

Bio

degr

adab

le p

olym

erPo

ly(la

ctic

aci

d),

poly

(gly

colic

aci

d), a

nd c

o-po

lym

ers9

,13,

57,1

06,1

07

The

lact

ic a

nd g

lyco

lic a

cid

poly

mer

s ar

e th

e m

ost w

idel

y us

ed s

ynth

etic

pol

yest

ers

for

abso

rbab

le im

plan

ts,

drug

del

iver

y, a

nd ti

ssue

eng

i-ne

erin

g. M

echa

nica

l deg

rada

-tio

n pr

oper

ties

can

be tu

ned

by v

aryi

ng p

olym

er s

egm

ents

.

Goo

d bi

ocom

patib

ility

Exc

el-

lent

wid

e ra

nge

of b

iode

gra-

detio

n ra

teG

ood

bior

esor

ptio

n

Poo

r wet

ting

prop

ertie

s re

sult

in

poor

dis

tribu

tion

of c

ell d

yrin

g se

edin

gD

egra

datio

n pr

oduc

ts a

re C

O2

and

H2O

, cre

atin

g lo

cal a

cidi

c co

nditi

onIn

flam

mat

ory

resp

onse

is p

os-

sibl

e P

oor s

tiffn

ess

and

com

pres

sion

stre

ngth

Bar

rier m

embr

anes

, dru

g de

liver

y, o

rthop

edic

app

lica-

tions

, gui

ded

tissu

e re

gen-

erat

ion

(in d

enta

l), s

tent

s,

stap

les,

sut

ures

, tis

sue

engi

neer

ing

B.1

.2Po

ly(e

thyl

ene

glyc

ol)9,

13,1

08,1

09

Use

d as

an

inje

ctab

le g

el,

mec

hani

cal d

egra

datio

n pr

op-

ertie

s ca

n be

tune

d by

var

ying

po

lym

er s

egm

ents

.

Bio

com

patib

le a

nd n

onto

xic

Hyd

roph

ilic

Ens

ures

uni

form

and

den

se

cell

seed

ing

Poo

r cel

l adh

esio

nP

oor m

echa

nica

l pro

perit

ies

Poo

r stif

fnes

s

Adi

pose

, bon

e , n

erve

car

ti-la

ge, l

iver

, hea

rt

B.1

.3Sy

nthe

tic p

olye

ster

s (P

lA, P

lGA

) and

col

lage

n bl

ends

57,5

8,11

0,11

1

The

spon

ges

of s

ynth

etic

po

lym

er w

ere

imm

erse

d in

a

colla

gen

sol u

nder

vac

uum

(to

fill

the

pore

with

col

lage

d so

lutio

n), t

hen

lyop

hiliz

ed a

nd

cros

slin

ked

by tr

eatm

ent w

ith

glut

aral

dehy

de.

Hig

h m

echa

nica

l stre

ngth

D

esire

d sh

ape

and

degr

ada-

tion

rate

Goo

d bi

ocom

patib

ility

and

cel

l in

tera

ctio

n

Sys

tem

ic o

r loc

al re

actio

ns

caus

ed b

y ac

idic

deg

rada

tion

prod

ucts

Adi

pose

, bon

e, n

erve

, car

ti-la

ge, m

uscl

es

Tabl

e 2.

Pro

pert

ies,

Adv

anta

ges,

Dis

adva

ntag

es, a

nd A

pplic

atio

ns o

f Syn

thet

ic B

iom

ater

ials

Use

d as

Sca

ffol

ds fo

r C

ell a

nd

Dru

g D

eliv

ery



Scaf

fold

N

o.Po

lym

ers

and

Prop

ertie

sA

dvan

tage

sD

isad

vant

ages

App

licat

ions

B.1

.4B

.1.4

.1A

lipha

tic/a

rom

atic

deg

rad-

able

pol

yest

ers

PPFs

111,

113

Line

ar p

olye

ster

with

a re

peat

-in

g un

it co

ntai

ns 2

est

er b

onds

an

d on

e un

satu

rate

d ca

rbon

ca

rbon

dou

ble

bond

.H

ydro

lysi

s of

the

este

r bon

d al

low

s P

PF

to d

egra

de, a

nd

degr

adat

ion

prod

ucts

of P

PF

have

bee

n sh

own

to b

e pr

i-m

arily

fum

aric

aci

d an

d pr

opyl

-en

e gl

ycol

.

Bio

com

patib

le a

nd b

iode

-gr

adea

ble

Ove

rcom

es th

e lim

itatio

n of

hy

drop

hobi

city

Slo

wer

deg

rada

tion

Min

imal

enc

apsu

latio

nLa

cks

mec

hani

cal s

treng

th

Orth

opae

dic,

bon

e,ca

rtila

ge, d

rug

deliv

ery

B.1

.4.2

PeT

Pb

T114

,115

Offe

rs th

e po

ssib

ility

of

man

ipul

atin

g hy

drop

hilic

ity

whi

ch is

an

impo

rtant

fact

or in

ce

ll ad

hesi

on a

nd g

row

th b

y ve

rifyi

ng th

e P

ET

cont

ent o

f th

e po

lym

er.

Bio

com

patib

le a

nd b

iode

-gr

adea

ble

Exc

elle

nt c

ell a

dhes

ion

Har

d to

pro

cess

and

con

trol

Arti

ficia

l ski

n,bo

ne ti

ssue

eng

inee

ring

B.1

.4.3

PHA

s57,

116

120

Phy

sica

l pro

perti

es in

clud

e no

nlin

ear o

ptic

al a

ctiv

ity

and

piez

oele

ctric

ity; i

.e.,

the

capa

city

of a

mat

eria

l to

suffe

r el

ectri

c po

lariz

atio

n du

e to

m

echa

nica

l stre

ss.

Bio

degr

adab

le a

nd h

ighl

y bi

ocom

patib

le T

herm

opla

stic

m

ater

ials

Hig

h br

ittle

ness

Pro

gres

sive

deg

ener

atio

nTi

ssue

eng

inee

ring,

dru

g de

liver

y, c

ardi

ac ti

ssue

en

gine

erin

g

B.1

.4.4

Pol

y(gl

ycer

ol s

ebac

ate)

121

123

This

pol

ymer

cla

ss c

an fo

rm

elas

tom

eric

and

toug

h bi

oma-

teria

ls. S

uppo

rts th

e gr

owth

of

a va

riety

of c

ells

, inc

ludi

ng fi

-br

obla

sts,

hep

atoc

ytes

, sm

ooth

m

uscl

e, e

ndot

he-li

al, c

ardi

ac

mus

cle,

and

Sch

wan

n ce

lls.

Bio

com

patib

le a

nd b

iode

grad

-ab

leH

igh

yiel

d Fa

bric

atio

n

Less

sta

ble

Live

r, ca

rdia

c

TAb

le 2

. (co

ntin

ued)


18 Garg et al.

TAb

le 2

. (co

ntin

ued)

Scaf

fold

N

o.Po

lym

ers

and

Prop

ertie

sA

dvan

tage

sD

isad

vant

ages

App

licat

ions

B.1

.5.

B.1

.5.1

Am

ine

grou

p co

ntai

ning

po

lym

ers

PAA

124

Con

tain

s te

rtiar

yam

ino

and

amid

o gr

oups

that

ar

e re

gula

rly a

rran

ged

alon

g th

eir p

olym

er c

hain

.

Hig

hly

vers

atile

C

ontro

lled

degr

ee o

f cro

ss-

linki

ng

Hig

hly

hydr

ophi

lic N

onto

xic

Inco

rpor

ates

pep

tide

or p

ro-

tein

stru

ctur

e

Hig

h de

grad

atio

n ra

teD

rug

deliv

ery,

cel

l del

iver

y,

orth

oped

ic, p

rote

in a

nd

pept

ide

deliv

ery

B.1

.5.2

N-s

ucci

nim

idyl

tar-

tara

te m

ono-

amin

epo

ly(e

thyl

eneg

lyco

lbl

ock

poly

(D,L

-lact

ic

acid

)125,

126

This

dib

lock

cop

olym

er

cons

ists

of a

bio

degr

ade-

able

lipo

phili

c po

lym

er b

lock

an

d a

hydr

ophi

lic b

lock

to

limit

or s

uppr

ess

the

nons

pe-

cific

ads

orpt

ion

proc

ess

and

conc

omita

nt d

isad

vant

ageo

us

side

effe

cts.

Bio

com

patib

leC

ontro

labl

e su

rface

com

posi

-tio

n C

ontro

labl

e ce

ll be

havi

or

Con

trola

ble

unde

sire

d pr

otei

n ad

sorp

tion

Diffi

cult

to p

roce

ss a

nd c

ontro

lD

rug

deliv

ery,

cel

l del

iver

y,

orth

oped

ic, b

one

B.1

.5.3

Poly

(dep

sipe

ptid

e-co

-lac-

tide)

127,

128

Has

pos

itive

or n

egat

ive

char

ges

exhi

bitin

g hi

gher

cel

l at

tach

men

t abi

lity.

Hig

h le

vel o

f con

trolla

ble

biod

egra

debi

lity

Con

trol o

f the

inte

ract

ion

with

liv

ing

cells

Diffi

cult

to m

aint

ain

stab

ility

for

long

er d

urat

ion

Dru

g de

liver

y, c

ell d

eliv

ery,

or

thop

edic

, bon

e, p

rote

in

and

pept

ide

deliv

ery

B.1

.6Po

ly(u

reth

ane)

s129

131

Tiss

ue-e

ngin

eere

d co

nstru

cts

mus

t exh

ibit

tissu

e-lik

e fu

nc-

tiona

lpr

oper

ties,

incl

udin

g m

e-ch

anic

al b

ehav

ior c

ompa

tible

to

the

nativ

e tis

sues

they

are

in

tend

ed to

repl

ace.

Goo

d m

echa

nica

l pro

perty

B

ioco

mpa

tibili

ty c

hara

cter

is-

tics

Con

trol o

f fibe

r dia

met

er, p

o-ro

sity

, and

deg

rada

tion

rate

Sm

all p

ore

size

sR

econ

stru

ctio

n of

bla

dder

m

uscl

e, e

ndot

heliu

m, v

as-

cula

r epi

thel

ial,

carti

lage



Scaf

fold

N

o.Po

lym

ers

and

Prop

ertie

sA

dvan

tage

sD

isad

vant

ages

App

licat

ions

B.1

.7Pl

uron

ic F

-127

(PeO

PPO

Pe

O)13

213

4

Cop

olym

er o

f PE

O a

nd P

PO

. P

luro

nic

F-12

7 is

bio

com

pat-

ible

hyd

roge

l with

sur

fact

ant

prop

ertie

s.

Stim

ulat

ed c

hond

rocy

te p

ro-

lifer

atio

n Im

prov

ed c

artil

age

mat

rix d

e-po

sitio

n in

term

s of

his

tolo

gy

and

bioc

hem

istry

Diffi

cult

to m

aint

ain

stab

ility

Car

tilag

e, a

s sc

affo

ld fo

r cel

l gr

owth

or a

s gr

owth

sup

-po

rting

filli

ng m

ater

ial

B.1

.8TD

P135

TDP

s w

ith a

n et

hyl e

ster

R

grou

p ha

ve b

een

show

n to

ha

ve fa

vora

ble

load

bea

ring

prop

ertie

s as

wel

l as

good

bo

ne a

ppos

ition

in v

ivo.

Suf

ficie

nt m

echa

nica

l stre

ngth

fo

r loa

d be

arin

g bo

ne fi

xatio

nTD

Ps

degr

ade

mai

nly

thro

ugh

carb

onat

e-hy

drol

ysis

to fo

rm 2

al

coho

ls a

nd C

O2,

so a

uto-

cata

lytic

deg

rada

tion

and

toxi

c ef

fect

s to

the

loca

l env

iron-

men

t pro

blem

s ar

e re

mov

ed

Deg

rade

s to

o sl

owly

(in v

itro)

Loss

in m

echa

nica

l stre

ngth

in

vivo

Orth

oped

ic s

caffo

ldap

plic

atio

ns

B.1

.9Po

lyor

thoe

ster

s136

Deg

rade

s th

roug

h th

e hy

dro-

lysi

s of

the

surfa

ce. B

y ad

ding

va

ryin

g am

ount

s of

lact

ide

segm

ent,

the

degr

adab

ility

of

thes

e po

lym

ers

can

be e

asily

tu

ned

from

15

100

days

.

Rat

e of

bre

akdo

wn

are

easi

ly

cont

rolle

dP

oor m

echa

nica

l pro

perti

esO

rthop

edic

, dru

g de

liver

y sy

stem

s, s

tent

s

B.1

.10

Poly

phos

phaz

enes

137,

138

Due

to th

e fle

xibl

e P

N b

ack-

bone

of p

olyp

hosp

h-az

enes

, re

sear

cher

s ha

ve a

sses

sed

the

scop

e of

this

pol

ymer

with

re

gard

s to

bot

h ha

rd a

nd s

oft

tissu

e en

gine

erin

g.

Bio

com

patib

le

Sup

ports

ost

eoge

nic

cell

grow

th (i

n vi

tro)

By

alte

ring

the

side

gro

ups,

ch

arac

teris

tics

such

as

crys

talli

nity

,deg

rada

bil-

ity, a

nd

hydr

opho

bici

ty c

an b

e va

ried

Deg

rada

tion

prod

ucts

of N

H3,

phos

phat

e, a

nd a

min

o ac

id

caus

e lit

tle h

arm

in v

ivo

Dru

g de

liver

y,sk

elet

al re

cons

truct

ion,

bone

rege

nera

tion,

wou

nd

dres

sing

,bl

ood

cont

actin

g de

vice

s

B.1

.11

Poly

anhy

drid

es13

9

Sur

face

ero

sion

pro

perti

esB

ioco

mpa

tible

, S

uppo

rt os

teog

enic

cel

l gr

owth

(in-

vitro

)

Mec

hani

cal s

treng

th m

uch

low

er th

an th

at o

f bon

eD

rug

deliv

ery,

Bon

e tis

sue

engi

neer

ing

TAb

le 2

. (co

ntin

ued)


20 Garg et al.

Scaf

fold

N

o.Po

lym

ers

and

Prop

ertie

sA

dvan

tage

sD

isad

vant

ages

App

licat

ions

B.1

.12

Poly

pyrr

ole1

40,1

41

Poly

pyrro

le h

as b

een

inve

sti-

gate

d as

a c

ondu

ctiv

e po

lym

er

that

cou

ld a

llow

sig

nal t

rans

-du

ctio

n to

take

pla

ce w

hile

the

nerv

e ce

lls a

re g

row

ing.

Its a

bilit

y to

be

easi

ly d

oped

so

its

wet

abi

lity

and

char

ge

dens

ity c

an b

e va

ried

to b

est

mim

ic n

eura

l stru

ctur

e

Hig

h co

st

Diffi

cult

proc

essi

ngLa

ck o

f mec

hani

cal s

tabi

lity

afte

r do

ping

Diffi

cult

to fa

bric

ate

Ner

ve ti

ssue

eng

inee

ring,

drug

del

iver

y,ce

ll de

liver

y,bo

ne ti

ssue

eng

inee

ring

B.1

.13

Poly

eth

er e

ster

am

ides

136

This

pol

ymer

is m

ade

up o

f a

soft

PEG

seg

men

t con

nect

ed

to a

har

d di

este

rdi

amid

e se

g-m

ent t

hrou

gh a

n et

her b

ond.

Ora

l and

par

ente

ral a

dmin

istra

-tio

nD

ifficu

lt to

fabr

icat

eH

igh

cost

Diffi

cult

proc

essi

ng

Test

ed fo

r tox

icity

B.2

.B

.2.1

Non

biod

egra

deab

le p

oly-

mer

sPo

lyvi

nyl a

lcoh

ol (P

VA)14

2 H

ydro

phili

c po

lym

er p

rodu

ced

by h

ydro

lysi

s of

pol

yvin

yl

acet

ate.

The

PVA

with

a

high

deg

ree

of h

ydro

lysi

s is

no

t sol

uble

in w

ater

at r

oom

te

mpe

ratu

re b

ut is

sol

uble

at

elev

ated

tem

pera

ture

s (u

su-

ally

abo

ve 7

0C

).

Mec

hani

cal s

tabi

lity

and

flex-

ibili

tyLi

mite

d du

rabi

lity

Deg

rada

tion

rate

not

con

trol-

labl

e

Cho

ndro

cyte

s, d

rug

deliv

-er

y, b

one

tissu

e en

gine

erin

g

B.2

.2PH

eMA

143

PH

EM

A is

a p

olym

er th

at

form

s a

hydr

ogel

in w

ater

.

Bio

com

patib

leH

igh

purit

yIn

duce

s hy

pers

ensi

tivity

reac

-tio

ns in

hum

ans

Brit

tle

Bon

e, c

artil

age,

drug

del

iver

y, c

onta

ct le

ns,

endo

vasc

ular

sur

gery

B.2

.3Po

ly(N

-isop

ropy

lacr

yl-

amid

e)14

3

Tem

pera

ture

sen

sitiv

e an

d ha

s a

sim

ulta

neou

sly

hydr

ophi

lic

and

hydr

opho

bic

stru

ctur

e th

at

dem

onst

rate

s a

low

crit

ical

so

lutio

n te

mpe

ratu

re a

t abo

ut

32o C

.

Mec

hani

cal s

tabi

lity

and

flex-

ibili

tyB

ioco

mpa

tible

Hig

h pu

rity

Diffi

cult

to m

aint

ain

stab

ility

for

long

er d

urat

ions

Text

ile in

dust

ry, m

edic

ine,

en

viro

nmen

tal fi

elds

, con

-tro

lled

drug

del

iver

y

PAA

, pol

y(am

ido

amin

e); P

BD

, pol

y(bu

tyle

ne te

reph

thal

ate)

; PE

O, p

olye

thyl

ene

oxid

e; P

ET,

pol

y(et

hyle

nete

reph

tala

te);

PH

A, p

olyh

ydro

xyal

kano

-at

e; P

HEM

A, p

olyh

ydro

xyet

hym

etha

cryl

ate;

PLA

, pol

y(la

ctic

aci

d); P

LGA,

pol

y(la

ctic

aci

dgl

ycol

ic a

cid)

; PPF

, pol

y(pr

opyl

ene

fum

arat

e); P

PO,

poly

prop

ylen

e ox

ide;

PVA

, pol

y vi

nyl a

lcoh

ol; T

DP,

tyro

sine

-der

ived

pol

ycar

bona

te.

TAb

le 2

. (co

ntin

ued)



Tabl

e 3.

Pro

pert

ies,

Adv

anta

ges,

Dis

adva

ntag

es,

and

App

licat

ions

of

Bio

cera

mic

s B

iom

ater

ials

Use

d as

Sca

ffol

ds f

or C

ell

and

Dru

g D

eliv

ery

Scaf

fold

N

o.Po

lym

ers

and

Prop

ertie

sA

dvan

tage

sD

isad

vant

ages

App

licat

ions

C.1

.C

.1.1

Cal

cium

pho

spha

te b

ased

Hyd

roxy

apat

ite58

,144

Fo

und

natu

rally

as

a co

mpo

-ne

nt o

f min

eral

phas

e of

bon

e.

Exc

elle

nt b

ioco

mpa

tibili

ty A

d-eq

uate

mec

hani

cal s

treng

thG

ood

oste

ocon

duct

ivity

Non

reso

rbab

leS

low

ly d

egra

dabl

eB

rittle

P

oor m

echa

nica

l pro

perti

es

Bon

e re

gene

ratio

n, b

one

and

carti

lage

, hea

rt an

d ne

rve,

ar

tifici

al s

kin,

liga

men

t and

de

ntal

, ren

al g

lom

erul

ar ti

ssue

, in

terv

erte

bral

dis

cC

.1.2

Tric

alci

um p

hosp

hate

145,

146

Com

posi

tiona

l sim

ilarit

y to

the

min

eral

pha

se o

f bon

e.

Exc

elle

nt b

ioco

mpa

tibili

ty A

d-eq

uate

mec

hani

cal s

treng

thB

iode

grad

able

G

ood

oste

ocon

duct

ivity

Poo

r mec

hani

cal p

rope

rties

S

low

ly d

egra

dabl

e (in

the

case

of c

ryst

allin

e st

ruc-

ture

)B

rittle

Bon

e an

d ca

rtila

ge, h

eart

and

nerv

es, a

rtific

ial s

kin,

liga

men

t an

d de

ntal

, ren

al g

lom

erul

ar

tissu

e, in

terv

erte

bral

dis

c, g

eni-

tour

inar

y tra

ct, v

ascu

latu

re,

wou

nd c

losu

re, c

ardi

ovas

cula

r, dr

ug d

eliv

ery,

ost

eoge

nic

dif-

fere

ntia

tion

C.2

bio

activ

e gl

asse

s an

d gl

ass

cera

mic

s (b

iogl

ass,

pho

s-ph

ate

glas

s)57

,106

Sho

w th

e ca

pabi

lity

to b

ond

to

both

bon

e an

d so

ft tis

sue

and

to s

timul

ate

bone

gro

wth

.

Goo

d bi

ocom

patib

ility

and

oste

ocon

duct

ivity

Tailo

rabl

e re

sorp

tion

Goo

d an

giog

enet

icA

dequ

ate

mec

hani

cal s

treng

th

Slo

wly

deg

rada

ble

(cry

stal

-lin

e st

ruct

ures

)B

rittle

(am

orph

ous

stru

c-tu

re).

Adi

pose

, car

tilag

e, b

one,

ne

rve,

ski

n, v

ascu

lariz

atio

n,

spin

al c

ord,

ost

eoch

ondr

al,

drug

del

iver

y


22 Garg et al.

Tabl

e 4.

Pro

pert

ies,

Adv

anta

ges,

Dis

adva

ntag

es, a

nd A

pplic

atio

ns o

f Com

posi

te B

iom

ater

ials

Use

d as

Sca

ffol

ds fo

r C

ell a

nd D

rug

Del

iver

ySc

affo

ld N

o.Po

lym

ers

and

Prop

ertie

sA

dvan

tage

sD

isad

vant

ages

App

licat

ions

D.1

Pol

ymer

-Cer

amic

13,5

8,14

7,14

8

Nat

ural

or s

ynth

etic

pol

ymer

s co

mbi

ned

with

cer

amic

s ar

e of

ten

used

for b

one

tissu

e en

gine

erin

g ap

plic

atio

ns.

Abi

lity

to ta

ilor m

echa

nica

l de

grad

a-tio

n an

d its

bio

logi

cal

prop

ertie

s

Fabr

icat

ion

tech

niqu

es

can

be c

ompl

ex

Bon

e an

d ca

rtila

ge, n

erve

, sk

in,

perio

dont

al b

one,

ost

eo-

chon

dral

, vas

cula

rizat

ion,

w

ound

dre

ssin

g, d

rug

deliv

ery

D.2

Pol

ymer

P

olym

er58

,147

,148

Com

bina

tions

of (

1) s

ynth

etic

sy

n-th

etic

, (2)

syn

thet

ic

natu

ral a

nd

(3) n

atur

aln

atur

al p

olym

ers

are

poss

ible

.

Goo

d bi

ocom

patib

ility

Goo

d os

teoc

ondu

ctiv

ity

Tailo

rabl

e de

grda

tion

rate

Im

prov

ed m

echa

nica

l pro

per-

ties

Com

prom

ise

betw

een

bes

t qu

aliti

es o

f ind

i-vi

dual

com

pone

nts

with

ov

eral

l sca

ffold

pro

perti

es

Bon

e an

d ca

rtila

ge, h

eart

and

nerv

es, a

rtific

ial s

kin,

lig

amen

t and

den

tal,

rena

l gl

omer

ular

tiss

ue, i

nter

ver-

tebr

al d

isc,

gen

itour

inar

y tra

ct, v

ascu

latu

re,

wou

nd c

losu

re, c

ardi

ovas

-cu

lar

PCL,

pol

ycap

rola

cton

e; P

EG, p

oly(

ethy

lene

gly

col);

PG

A, p

olyg

lyco

lic a

cid;

PLG

A, p

oly(

lact

ic a

cid

glyc

olic

aci

d); P

LA, p

oly(

lact

ic a

cid)

; PLL

A,

poly

- l-la

ctic

aci

d.



V.A. EMULSIFICATION/FREEzE-DRYING METHOD

The freeze-drying technique is use for fabrication of porous scaffolds. This technique is based upon the principle of sublimation. Scaffolds are generally prepared by dissolving/suspending polymers/ceramics in water or in an organic solvent followed by emulsifica-tion with a water phase. After pouring this mixture into a mold, solvents are removed by freeze-drying and porous structures are obtained (Fig. 3).150,151

Freeze-drying is conducted by freezing the material

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