With the passage of time and the development of new technologies, there has been a paradigm

shift from finding replacements/substitutes to human tissue to trying to have the lost human
tissue re-grow. This shift in paradigm has led to the development of a new area of research
know as 'Tissue Engineering'.

BIOMATERIALS
Dhirendra Katti

Biomaterial Science is the physical and

biological study of material and their
interactions with the biological environment.
This science has gradually evolved to become
an independent science under the broad area
of bioengineering. Althought it does not have
a long history associated with it being regarded
as an independent area, 'biomaterials' per se
have been in existence since the desire of a
clinician to repair damaged human tissue.
Classically biomaterials have been used as
substitutes for human tissue and hence were
supposed to be inert and mechanically strong,
for example, gold used as substitutes of
human teeth, and the Jaipur foot used as an
artificial foot for amputated limbs. With the
passage of time and the development of new
technologies, there has been a paradigm shift
from finding replacements/substitutes to
human tissue to trying to have the lost
human tissue re-grow. This shift in paradigm
has led to the development of a new area of
research know as 'Tissue Engineering'. Tissue
engineering can be defined as the application
of principles and methods of engineering and
life sciences towards the fundamental
understanding of str ucture-function
relationships in normal and pathological
mammalian tissue and the development of
biological substitutes to restore, maintain, or
improve tissue function [1].
One of the focuses of our work is engineering
of cartilage tissue, more specifically articular
cartilage tissue (i.e. the cartilage tissue of the

Department of Biological Sciences

& Engineering

joints). The degeneration of articular

cartilage and associated arthritis
(osteoarthritis and rheumatoid arthritis) is
among the most prevalent chronic condition
in India and the world over. In osteoarthritis,
the cartilage covering the joint gradually
wears away, exposing the bone which in turn
makes joint motion difficult and painful. The
condition is plagued by two major drawbacks
(i) The regenerative capacity of cartilage
tissue is limited due to the sparse population
of chondrocytes, reduced presence of
progenitors and the avascular nature of the
tissue, and (ii) The repaired tissue that is
formed is a combination of hyaline and
fibro-cartilage that has poor mechanical
properties when compared to native articular
cartilage and also tends to degrade over time.
The conventional methods of treating
osteoarthritis / damaged cartilage tissue are
(i) 1st line of treatment is drug therapy
wherein most often anti-inflammatory drugs
and analgesics (pain killers) are used, (ii) 2nd
line of treatment is surgical intervention /
manipulation which involves approaches
such as autolog ous chondrocyte
implantation (ACI), subchondral drilling,
mosiacplasty, and allografts, and (iii) 3rd line
of treatment is total knee replacement
wherein the arthritic knee is replaced with an
artificial knee. The 1st line of treatment
provides only symptomatic relief. The 2nd
line of treatment, although fairly successful,
often leads to the formation of fibrocartilage
that is mechanically inferior to articular
cartilage. The 3rd line of treatment is a

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potential solution, however, it involves a major

surgical procedure and the implants are very
expensive. In addition, the life of a knee
replacement implant is in the range of 10-15
years. The limitations associated with the
current treatment options have prompted
researchers and clinicians to look for better
alternatives. Tissue engineering provides an
opportunity to overcome the limitations
associated with conventional methods of
treating loss of cartilage tissue. The tissue
engineering strategies primarily involve the
combination of three components (i)
scaffolding system, (ii) cells (tissue specific or
progenitors) and (iii) cell signaling molecules
(growth factors) (Figure 1).

reservoir for growth factors that can be

delivered locally for a specific duration at an
appropriate rate. Cartilage tissue is made up of
a small population of cartilage cells
(chondrocytes) and largely extra-cellular matrix
(ECM) that is in turn mainly made up of type II
collagen and glucoaminoglycans (GAGs).
These exctracellular matrix components are
fibrous in nature and have diameters that are in
nanometer scales. Therefore, our approach has
been a biomimetic one, wherein, we propose to
develop nanofibrous 3-D scaffolds that mimic
the type II collagen and GAG fibrils. The
nanofiberous scaffolds can be fabricated using
the electrospinning technique that involves the
application of a high potential to a polymer

Figure 1: A schematic diagram depicting the various stages involved in the process of Tissue Engineering
(Reprinted with permission from publishers of Directions, IIT -Kanpur).

The scaffolding system is central to the tissue

engineering strategy as they provide cells with a
surface for adherence and 3-dimensional (3-D)
growth. Also, the scaffolds can be used as a

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solution to enable the formation of nanofibers

(Figure 2 on page 106).
In this procedure the polymer solution is held

Syringe
Grounded
Substrate

Needle

Polymer
Solution
Polymer Jet
HV Power Supply

Figure 2: A cartoon showing the electrospinning process (image not to scale).

at the tip of a needle by virtue of its viscosity.

The polymer solution is then provided with a
voltage potential that in turn provides charge to
the polymer solution. As the potential is
gradually increased the charge density on the
polymer solution increases and eventually leads
to columbic repulsion. When the repulsive
forces exceed the viscous forces of the
polymer, a jet ensues from the tip of the needle
that initially has a straight path and then
undergoes instabilities to traverse a spiral path
with increasing diameter. This trajectory of
the jet allows for continuous thinning of the
polymer jet as well as evaporation of the
solvent from the jet, eventually leading to the
formation of charged dry nanofibers that are
collected on a grounded metallic collector.
The fibers obtained using the electrospinning
technique can be altered both in terms of
morphology and diameter via modifications in
the fabrication parameters. The morphology
can vary from elliptical bead containing fibers

to smooth fibers and the diameters can range

from 10's of nanometers to 1000's of
nanometers. Our group has focused on the
development of nanofiber-based scaffolding
systems for the purpose of cartilage tissue
engineering. In one approach we propose to
use the nanofibrous scaffolds as growth factor
delivery systems, wherein the growth factors
will be linked to the scaffolding system
covalently using a linker molecule. This system
when implanted into an arthritic knee will be
exposed to proteases (enzymes that selectively
cleave specific bonds) that will cleave the
covalent bond that connects the growth factor
to the nanofibrous scaffold, thereby leading to
the release of the growth factor. It is expected
that the released growth factor will then
provide the necessary signaling to enable
enhanced cell proliferation and function.
Some of the nanofiber systems that we have
been successful in synthesizing are shown in
Figure 3 on page 107. These nanofiber systems

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(a)

(b)

(c)

Figure 3: Scanning elec tron micrographs of ele ctrospun nanofibers made fr om (a) poly(lactic ac id) - scale bar
20m, (b) polystyre ne sc ale bar 10m, and (c) poly(lactide-co-glycolide) - scale bar 100m.

can be potentially applied to other applications

such as filter media, sensors, electrically
conducting nanofibers, optical applications,
material reinforcement, protective clothing
and cosmetics.
Another major focus of our group has been on
the development of drug delivery systems.
Drug delivery systems are devices that can
carry bioactive molecule to a target tissue and
deliver the same at a specific rate and for a
predetermined duration. The advantage of
such a system is that it improves the
bioavailability of the bioactive molecule
delivered, restricts the desired action to the
target tissue, reduces the potential side effects
involved and eliminates repeated dosing.
These systems can provide improved patient
compliance especially in cases of toxic drugs
such as those used in chemotherapy.
One of the goals of our group is the
development of degradable polymer-based
drug delivery systems. The impetus for using
degradable polymers is that once the delivery
vehicle is administered in vivo, the need for a
second procedure to recover the delivery

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system is not necessary if the delivery system is

degradable. It is expected that the delivery
system would perform its function and then
degrade inside the human body with the
degradation products being metabolized in the
human body. One such system that we are
currently working on is a degradable polymerbased nanoparticle drug delivery system for the
treatment of lung cancer.
Cancer is a global health problem of grave
dimensions. Amongst all the cancer types, lung
cancer is the leading cause for cancer related
deaths worldwide [2]. The grim prognosis
associated with lung cancer has prompted us to
study the pitfalls of the existing treatment
modalities and hence hopefully arrive at
potential solutions.
Lung cancer is of two types: small cell lung
cancer (SCLC) and non-small cell lung cancer
(NSCLC) [3]. Treatment for lung cancer can
involve either surgical removal of tumor,
chemotherapy, or radiation therapy, or an
appropriate combination of these methods [2].
Amongst these, chemotherapy is the treatment
of choice for SCLC and advanced stages of

surgically non-resectable NSCLC [3].

One of the reasons for sub-optimal
chemotherapy that holds true for lung cancer
and most solid tumors is that, systemically
administered chemotherapeutic agents are not
particularly efficient in providing appropriate
quantities of the chemotherapeutic agent at the
tumor site [4]. This can be attributed to the
demarcating differences between a tumor and a
normal tissue. Tumors are unique in terms of
the following characteristics (a) the interstitialpressure is greater at the core in comparison to
the tumor periphery thus decreasing the drug
penetration and hence concentration in the
tumor core,
(b) the erratic vasculature
hampers drug delivery inside the tumor, (c) the
rigidness of the tumor extra-cellular matrix
decreases the permeability/distribution of
antineoplastic drugs uniformly across the
tumor, (d) the property of the tumor cells to
be in different phases of cell cycle and to have
different doubling times may not be favorable
for anti-cancer agents as many of them are
phase specific, (e) the tumor size also
influences the outcome of the chemotherapy
as the inner core may not be accessible to drugs,
at all, in big tumors, and (f) location of a tumor,
like that inside the brain is inaccessible to most
anti-cancer agents. These parameters in
combination make systemically administered
chemotherapy a sub-optimal therapy.
A potential solution to all the aforementioned
problems could be intratumoral delivery of
sustained releasable cancer-chemotherapeutics
which enhances antitumor activity by focusing
therapy at the tumor site [3]. In our group we
propose to achieve this using degradable
polymeric devices of micro- to nanodimensions, which slowly release the
encapsulated agent after implantation into

tumor tissue, providing the opportunity to

introduce large quantities of an anticancer
agent directly at a tumor site for a prolonged
period. Since this approach involves the local
administration of drugs, systemic toxicity can
potentially be circumvented.
The limited literature available on intratumoral
deliver y systems sug gest that single
chemotherapeutic drug based systems are
insufficient for complete tumor regression.
However, it has been firmly established that
combination therapy of two or more
chemotherapeutic agents can be more effective
than a single agent [5, 6]. The advantages of
combination therapy are (i) Tumor cell death in
a heterogenous tumor cell population can be
achieved in a more effective way when drugs
working on different principles are combined,
and (ii) The synergism between drugs would
enable a reduction in total dose of each drug
necessary for tumor ablation, thereby leading
to reduced dose related toxicity, improved
patient compliance and cost-effective
treatment. To achieve the aforementioned
a d v a n t a g e s, p r e v i o u s s t u d i e s h a v e
demonstrated that sequential administration is
more effective than simultaneous delivery [5,
6]. Therefore, we propose a sequential
administration of two chemotherapeutic
agents Paclitaxel (a microtubule interfering
agent) and Topotecan (a topoisomerase 1
inhibitor). The goal is to develop a micro to
nanometer scale polymeric particle-based
intratumoral delivery system that sequentially
releases encapsulated drugs paclitaxel, followed
by a drug free period which is further followed
by the release of topotecan. Towards this goal
we have synthesized biodegradable micro- and
nano-particles using the electrospraying
technique. This technique is a modification of
the electrospinning technique that involves the

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Figure 4: Scanning electron micrograph

of chitosan micro/nanoparticles synthesized
using the electrospraying technique.

usage of a dilute polymeric solution that is

provide with a high voltage potential that allows
for the atomization of the polymer solution to
form micro- nano-particles. An image of these
particles generated using the aforementioned
technique are shown in Figure 4 above. These
nanoparticulate systems can be potentially
applied to other applications such as
diagnostics, MRI contrast agent delivery, and
for improved efficiency of coolants by
suspending metallic nanoparticles in heat
exchange fluids.
Overall, our work involves the application of
biomaterials, more specifically polymeric
biodegradable biomaterials, for two focused
areas of bioengineering tissue engineering and
drug delivery systems. The future of
biomaterials seems very bright as we see it
today, however, a large responsibility rests on
the shoulders of the professionals working in
this multidisciplinary area. In conclusion, I will
quote what I had on the last slide of my

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presentation at REACH 2007 An appropriate

combination of engineers, clinicians and basic
science researchers will pave the way for the
development of better biomaterials and hence
(medical) devices that will help improve the
quality of human lives.
References
1. Y.C. Fung and R.C. Skalak in the First
symposium on tissue engineering sponsored by
the NSF, USA (1987).
2. Behera D.,Balamugesh T. Lung Cancer in
India. Indian J Chest Dis Allied Sci.,46:269-81(
2004 ).
3. Kasper D.L., Bruanwald E., Fauci A.S.,
Hauser S.L., Longo D.L., Jameson J.L.
Harrison's Principles of Internal Medicine,
16th Edn, Neoplasms of the lung, 506-516 .
4. Torchilin V.P. Drug targeting. European
Journal of Pharmaceutical Sciences, 11:S81-S91
(2000).
5. Ning Y. Y., Patawaran M.B., Chen J.Y.,

Orenberg E.K., Brown D.M., Luck E.E.

Influence of treatment sequence on efficacy of
flurouracil and cisplatin intratumoral drug
delivery in vivo The Cancer Journal From Scientific
American, 1: 215-221 (1995).

6. Sengupta S., Eavarone D., Capila I., Zhao

G., Watson N., Kiziltepe T., Sasisekharan R.
Temporal targeting of tumour cells and
neovasculature with a nanoscale delivery
system. Nature, 436: 568-572 (2005).

Prof. Dhirendra S. Katti is a Ph.D from the University of Mumbai. His

research interests are Tissue engineering; Controlled drug delivery
system & Biomaterials.

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