Scsi journal april 2016 final volume 2

Indian Journal of Stem Cell Therapy
Volume 2, Issue 1, April 2016
The official journal of Stem Cell Society (India)

2 Indian Journal of Stem Cell Therapy
Founder
Dr. Alok Sharma
Editor-in-Chief
Dr. Nandini Gokulchandran
Associate Editors
Dr. Rohit Kulkarni, Dr. B.S. Rajput, Dr. Prabhu Mishra, Dr. Asha Sakolkar
Editorial Board
Dr. Yogesh Agarwala Dr. Prerna Badhe
Dr. Anant Bagul Dr. Parikshit Bansal
Dr. H. S. Bedi Dr. M. Chaturvedi
Dr. Subhadra Dravida Dr. Mayank Jain
Dr. Rupam Jain Dr. Shrada Jain
Dr. Rajan Joshi Dr. Manish Khanna
Dr. Pradeep Mahajan Dr. Chandramani More
Dr. Shankar Narayana Dr. Deepak Puri
Dr. Raghavan Ramakutty Dr. Hemangi Sane
Dr. Anand Srivastava
Assistant Editors
Dr. Richa Bansod
Ms. Pooja Kulkarni Dr. Amruta Paranjape (PT)
Editorial Policy :
The Indian Journal of Stem cell Therapy is committed to maintaining the highest level of integrity in the content published. Content
published in this journal is peer reviewed.
The journal accepts original research articles, letter to editor, review articles, case reports, editorials, short communications, etc. on all the
aspects of stem cells. The Editorial Team contributes to the editorial and decides about the publication of proceedings of scientific
meetings and other contributions such as Book Reviews, etc. Editors manage the whole submission/review/revise/publish process. All
submitted manuscripts are reviewed and scrutinized initially by the office of the editor.
Manuscripts are evaluated according to the following criteria:
• Originality of the Material
• Clarity in Writing
• Appropriateness of the Language and Style
• Validity and logic of the Study methods, data and the statistical methods
• Support of the Conclusion by reasonable data
• Significance of the information from the reader's perspective
• Compliance of the manuscript with the focus and scope of the journal.
Manuscripts satisfying the above criteria are sent for formal peer-review to usually three reviewers, but sometimes more in special
circumstances. The office of the editor then makes a decision based on the reviewers' suggestion. Peer reviewer identities and author
identities are kept confidential. The manuscript under review is not revealed to anyone other than peer reviewers and editorial staff.
Reviewers, whose names are not disclosed to the authors, will study all contributions, which the editor sends for peer review after
considering them to be of sufficient significance and interest.
Neither acceptance nor rejection constitutes an endorsement by the journal of a particular policy, product or procedure.

Indian Journal of Stem Cell Therapy 3
Contents
1. From the Editor's Desk .... 4
2. Current global trends in regulations for stem cell therapy and .... 5
the way ahead for India
Alok Sharma, Nandini Gokulchandran, Hemangi Sane, Prerna Badhe, Amruta Paranjape
Anthropologist commentary
3. Stem Cell terrains in India: An Anthropologist explores .... 17
Nayantara Sheoran
Case Reports: One Step At a Time
4. A novel cell based treatment for Avascular Necrosis of femoral head -
A case report .... 21
Pradeep V. Mahajan, Prabhu Mishra, Anurag Bandre,
Swetha Subramanian, Manu Menon, Neetin Desai
5. Treatment of Knee Osteoarthritis with Autologous Bone Marrow
Derived Mesenchymal Stem Cells - A case report .... 25
Rohit Kulkarni, Abhijit Bopardikar, M. Dhanasekaran
6. Neurorestoration in Amyotrophic Lateral Sclerosis - A case report .... 29
Hemangi Sane, Alok Sharma, Nandini Gokulchandran, Sarita Kalburgi,
Amruta Paranjape, Prerna Badhe
7. Chronic Cervicitis: Role of Adult Autologus Stem Cells .... 38
Dr. Sapna Jain, Dr .Mayank Jain
8. Autologous Buccal Pad of Fat Stromal Vascular Fraction Used
To Regenerate Larger Defect Due to Maxillary Dentigerous Cyst .... 43
K. Manimaran, K. Arunkumar, Chandramohan, S. Mahenderaperumal,
S.Sankaranarayanan, D. Avinash Gandi, Rohini Sharma
Possibilities – A Literature review on Liver Cirrhosis
9. Role of Autologous Bone Marrow derived
Mononuclear Cells in Liver Cirrhosis .... 49
Prabhu Mishra, Sharda Jain, Shagufta Parveen, Zohra Khatoon
From the Researchers Dish
10. Human adipose tissue-derived stem cells differentiate to
neuronal-like lineage cells without specific induction .... 55
Omana A. Trentz, Subathra Kamalakannan, Vinoth K. Parthasarathy,
Visvanathan Krishnaswamy
From the Clinicians Quiver
11. Cellular therapy in Neurodevelopmental disorders .... 64
Dr. Alok K. Sharma, Dr. Hemangi Sane, Ms. Pooja Kulkarni,
Dr. Nandini Gokulchandran, Dr. Prerna Badhe

From the Editor's Desk........''We judge ourselves by what we feel capable of doing, while others judge us by what we have already
done.''- Henry Wadsworth Longfellow (1807-1882)
Politicians and media are quick to describe researchers of different stem cell types as opposed to each
other's work, depicting the main dynamic among researchers and clinicians as antagonistic. The truth
is that a breakthrough in one area of stem cell research advances the knowledge base of the entire field
(Howe et al) and encourages the scientific enthusiasm in all stakeholders. The idea is not to sidestep
ethical considerations but to bring about a healthy discussion on the possibilities and pitfalls of stem cell
research.
For this edition, we have an anthropologist provide her point of view on Stem Cell Therapy in India.
It is a neutral perspective from someone who is neither a part of the scientist community nor a part of
a traditionalist viewpoint and, therefore, a welcome prospect. An insight into the expectations of patients,
the position of scientists/physicians in India to provide cures for their suffering patients as also the policy
makers' point of view to drive to ensure safety and efficacy of treatments for patients at ethically viable
costs is provided.
India is now emerging as the global leader in the transformation of stem cell research and in keeping
with the aim of The Indian Journal of Stem Cell Therapy as a scientific forum to assimilate new
information in stem cell research and cellular therapy happening in India and facilitate its dissemination
to the global community, we have a study on stem cell therapy on Avascular necrosis (AVN) on the
Femoral head. With AVN of femoral head effecting estimated 10,000-20,000 new cases per year in the
United States alone, the study explores intra-articular injection of autologous stem cells.
Another debilitating illness, osteoarthritis, is one of the most common diseases, and affects 12% of the
population around the world. Bone Marrow derived Mesenchymal Cells applied in animal models show
encouraging results in modulating inflammation and joint cartilage repair. A treatment option of
Autologous Bonemarrow Derived Mesenchymal stem cells is discussed in a case study showing a
potential for stem cell therapy of osteoarthritis.
Reduction in synaptic plasticity and subsequent generation of incorrect synaptic connections between
neurons are the major concern in Neurodevelopmental Disorders. The functional improvement after
stem cell transplant in a study involving 371 children with NDDs encourages the scientific community
to further explore the improved plasticity of the nervous system. An ALS case report demonstrates that
autologous BMMNC intrathecal transplantation has a great potential as a novel therapeutic modality.A
new study explores the use of autologous buccal pad of fat-stromal vascular fractions for the treatment
of dentigerous cyst to treat larger defect involving right maxilla due to the cyst involving maxillary
sinus.
We are looking forward to bringing forth more research and discussion on stem cell therapy in India
and taking a leap forward towards revolutionizing healthcare by ethical means.
Dr. Nandini Gokulchandran

Current global trends in regulations for stem cell therapy and
the way ahead for India
Dr. Alok Sharma MS, M.Ch.; Dr. Nandini Gokulchandran MD; Dr. Hemangi Sane MD.;
Dr. Prerna Badhe, MD.; Dr. Amruta Paranjape (PT)
Affiliations: NeuroGen Brain and Spine Institute, Navi Mumbai, India
Abstract
In the last issue of this journal we had published an article 'The need to review the existing
guidelines and proposed regulations for stem cell therapy in India based on published scientific
facts, patient requirements, national priorities and global trends' on the need of new regulation
for Stem Cell therapy in India. We had highlighted the deficiencies in the existing guidelines and
suggested broad general principles on which new regulations should be framed. Worldwide
countries have realized the need for newer regulations that are more permissive of stem cell
therapy. Most progressive legislation is that of the USA ( REGROW Act) and JAPAN (PMD
Act and ASRM), which allows conditional, fast track marketing approval for stem cell products
and separate monitoring systems for cell therapies based on their risk to human life and health.
The Korean Regulations have excluded minimally manipulated cells from their 'Review and
authorization of Biological products'. European medical agency (EMA) has also come up with
the advanced therapy medical product (ATMP) laws, PRIME (PRIority MEdicines) act and
Hospital Exceptions (HE) act that are also favourable to newer therapies such as regenerative
medicines. New concepts and terms that are now becoming part of the more permissive regulations
are Conditional marketing approval, Risk Stratification, Post-Hoc efficacy analysis, Presumed
efficacy, Patients' right to seek treatment, Distinction between cellular therapies, Distinction
between a stem cell product and medical service.
In sharp contrast to this, in India the latest guidelines made by Indian council of Medical Research
(ICMR) are moving backward and are in the process of trying to implement policies that will
completely destroy the stem cell therapy field in India. The Major limitation in the current
guidelines is that the ICMR does not differentiate between a product and a medical service. The
current regulatory policies which are in favor of corporates who can spend large amounts of
money and which discourages or prevents those who cannot spend large amounts of money is not
in the national interest of our country.
In this paper we elaborate on a road map that Indian regulators should take in order to facilitate
easy availability of cellular therapies to patients suffering from incurable disease but ensuring at
the same time that only safe therapies are provided. We suggest that there should be 3 categories;
Researchers who would be regulated under ICMR guidelines, Corporate stem cell product
manufacturers who would follow Central Drug Standard Control Organizaion (CDSCO)/ Drugs
controller general (India) [DCG(I)] do therapy subject to IEC approval, Medium risk cell therapy
providers such as more than minimally manipulated allogeneic would in addition need approval
from IEC and CDSCO and those using high risk cell therapies such as embryonic and iPSCs
would need IEC, CDSCO and ICMR approval.
We conclude that the ministry of health along with ICMR and CDSCO need to study the REGROW
Act of USA as well as the Japanese and Korean legislations for regenerative medicine and come
up with a definitive set of regulations which are permissive of medical practitioners offering safer
forms of cellular therapies like autologous and minimally manipulated therapies and stricter
regulations for more unsafe cellular therapies and corporates producing and selling stem cells as

Introduction:
Over the last century in the field of medical
practice there were two broad categories of
regulations first for drugs and devices and second
for medical procedures. Whereas drugs and
devices have always been heavily regulated,
medical procedures by and large did not come
under the purview of regulators and it was left
to individual physicians and surgeons to offer to
their patients what in their view was the best
medical practice. The evolution of stem cell
therapy has created a peculiar problem because
there are stem cell therapy related medical
products as well as stem cell therapy that are
offered as medical service. This has created a
situation where it is difficult to have regulations
for cellular therapy that are as strict as those for
drugs and medical devices but at the same time
give freedom and flexibility to medical
practitioners to offer this as medical service. This
difficulty has led to very strict regulations in
countries where Stem Cells are considered as a
biological product and therefore stem cell
therapies are not available in such countries and
on the other hand in some countries stem cell
therapy are being offered without oversight.
In the last issue of this journal we had published
an article 'The need to review the existing
guidelines and proposed regulations for stem cell
therapy in India based on published scientific
facts, patient requirements, national priorities and
global trends' on the need of new regulation for
Stem Cell therapy in India.(1) We had highlighted
the deficiencies in the existing guidelines and
suggested broad general principles on which new
regulations should be framed. We reviewed the
regulations of different countries and compared
it with the current regulations in India. Various
dissimilarities were highlighted and suggestions
for the changes in the Indian guidelines were
made based on the regulations in other countries.
In the current scenario countries worldwide have
realized the need for newer regulations that are
more permissive of stem cell therapy.
In the one year since we wrote the article, the
most dramatic transformation is happening in the
USA where a completely new law called the
Reliable and Effective Growth for Regenerative
Health Options that Improve Wellness Act
(REGROW Act) is under consideration by their
Senate.(2)
Evolution of regulatory framework for
regenerative medicine in the United States
of America (USA)
The original guidance regarding use of tissue
products was drafted and approved in 1996. In
the subsequent year (1997) a separate code of
federal regulation (CFR) 1271 was drafted to
regulate these products. (3) These were classified
under Human cells and tissue and cellular and
tissue based products HCT/Ps in this CFR which
made a clear distinction between a 'drug' which
is a chemical molecule from these biological
products. The products were further classified as
biological products or medical devices based on
difference criteria and a separated set of
regulations was drafted for both.These guidelines
took into consideration the differences not only
between the type of cells but also between the
procurement procedures and routes of
administration that may significantly alter the
safety and efficacy profile of the cells. Although
the classification was primitive and inadequate,
it was based on the available body of evidence
and existing trends and concepts for monitoring
development of new therapeutic drugs. The
products were classified into; minimally
manipulated cells, defined as, cells that do not
alter their relevant biological characteristics (due
to the technique and/or chemicals used to
procure them) and more than minimally
manipulated cells. The regulations also
differentiated between the route of
a product. This will result in only safe treatments being available as therapy and at the same time
ensure that patients suffering from serious medical conditions are not deprived of stem cell therapies
that can help them.
Key words: Stem cell therapy, cellular therapy, regulation, conditional marketing approval,
presumed efficacy, compassionate use, Helsinki declaration, Japan regulations, Korea regulations,
REGROW ACT.

administration as homologous and non-
homologous use. Homologous use was defined
as the repair, reconstruction, replacement, or
supplementation of a recipient's cells or tissues
with an HCT/P that performs the same basic
function or functions in the recipient as in the
donor.
These products were regulated by 2 governing
laws, first, Public health services act (PHS) which
mandated that any new biological product for
licensing will be required to produce the data
from clinical study or studies that demonstrate
the safety, purity and potency of the cells. (4)
However, the guidelines did not define what type
of studies or number of patients will be
considered appropriate for demonstrating this.
The 21CFR 1271.15 clearly stated that minimally
manipulated cells used for non-homologous use
will be exempted from the regulatory
requirements of FDA for marketing approval if
the cells and procured and transplanted in the
same surgical procedure. Another provision in
the 21CFR 601.40 allowed for the accelerated
approval for serious or life threatening illness. This
was applicable to certain biological products that
had been studied for safety, efficacy and provided
meaningful therapeutic benefit to the patients
over existing treatment. In accordance with these
guidelines various autologous regenerative
medicine products that were used for
homologous use were approved and licensed in
USA between1997 to 2011.
Between the years 2011 and 2015 in the view of
growing clinical evidence for stem cell therapy,
Right to try act was designed. Although the
regulations prevented generalized marketing of
regenerative medicine products up till 2015, after
the introduction of Right to try act marketing of
experimental drugs for the terminally ill patients
was allowed on a case by case review basis.(5)
The act quoted, Notwithstanding the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 301 et
seq.), the Controlled Substances Act (21 U.S.C.
801 et seq.), and any other provision of Federal
law, the Federal Government shall not take any
action to prohibit or restrict the production,
manufacture, distribution, prescribing,
dispensing, possession, or use of an experimental
drug, biological product, or device that (1) is
intended to treat a patient who has been
diagnosed with a terminal illness; and (2) is
authorized by, and in accordance with, State
law.
Recently based on the growing clinical evidence
for the use of cellular therapy for the treatment
of various incurable disorders, Senator Mark Kirk
introduced a bill to amend the Federal food, drug
and cosmetic act; in front of committee on Health,
Education, Labor and Pensions, in 114th congress
of the American senate. The amendment was
named Reliable and Effective Growth for
Regenerative Health Options that Improve
Wellness act, REGROW Act. (2)REGROW act
alters the current regulatory framework to
provide conditional marketing approval to
minimally manipulated cells for non-homologous
use and more than minimally manipulated cells
without going through the formal procedure of
approval as per section 351 (A) of part F of Title
III of PHS law. Subsequently it is required that
the licensing application be filed in the next 5
years, based on the post marketing research, as
per section 351 (A) of part F of Title III of PHS
law. The cells and products exempted under these
conditions are described in detail in the REGROW
act as,
(1) Such cells or tissues are adult human cells or
tissues.
(2) Such cells or tissues have been evaluated to
examine immunogenicity and do not provoke a
significant unintended immune response in the
recipient.
(3) Such cells or tissues are -
a. minimally manipulated for a non-
homologous use; or
b. more-than-minimally manipulated for a
homologous or non-homologous use, but
are not genetically modified.
(4) Such cells or tissues are produced for a specific
indication.
(5) Such cells or tissues are produced exclusively
for a use that performs, or helps achieve or re-
store, the same, or similar, function in the
recipient as in the donor.
(6) Within 5 years of the safety and effectiveness
determination described in his section, the
sponsor of the conditionally approved new

product prepares and submits an application for
approval of a biological product under section
351(a), demonstrating potency, purity, safety,
and efficacy of the use. The Secretary may permit
continued use of such product until the Secretary
completes the review of the application and
makes a determination. Upon a determination
by the Secretary not to approve the application,
use of the cellular therapeutic shall not be
permitted.
(7) During the conditional approval period and
before approval of an application under section
351(a), the sponsor shall prepare and submit
annual reports and adverse event reports to the
Secretary containing all the information required
for approved biological products.
(8) The sponsor has submitted an application under
section 505(i) of the Federal Food, Drug, and
Cosmetic Act for the treatment of the patients
during the 5-year conditional use period.
(9) The sponsor has not previously received
conditional approval for such product for the
same indication.
Although REGROW Act is uniformly applicable
to stem cell products as well as stem cell
therapies the highlight of this act is A] Conditional
marketing approval and B] Provision for post-
hoc efficacy analysis. (2) This relieves the burden
of the evidence from newer upcoming cellular
therapies and products. It allows medical
innovators and practitioners to develop promising
therapies without having to go through phased
approval process as before. The proposed law has
created criteria to protect patients from unsafe
therapies. This ensures easy and faster availability
of promising cell therapies to patients that can
benefit from them without any risk of adverse
effects.
Once this law is implemented the principles of
Conditional marketing approval and Provision
for post-hoc efficacy analysis will become part of
the regulations.
Evolution of regulatory framework in Japan
Japan took the first big step in 2014 when they
modified their already existing medical law,
Pharmaceuticals Affairs Law (PAL) through a
partial amendment named as Pharmaceuticals
and Medical Devices Act (PMD Act) under the
act on promotion of regenerative medicine. (6)
Till 2014 there was no statutory body in Japan
for monitoring regenerative medicinal products.
All the medicinal drugs and products were
regulated under the general pharmaceutical
regulations. In the same year another law that
was formulated and implemented, Act on Safety
of Regenerative Medicine (ASRM).(7) ASRM
safeguarded the patients from unsafe cellular
therapies. In these two laws they have made a
clear distinction between the companies that
make stem cell products, institutes that offer
medical services and medical research. They have
introduced the concept of conditional marketing
for medical products and separate approval
systems based on the risk stratification for the
medical services. This for the first time ensured
separate legislation for stem cell therapy products
and medical devices and stem cell therapies
offered as a treatment by individual practitioners
and institutes.
When looking at the Japanese regulations,
following points stand out
(A) Regulations for the product
(B) Regulations for the medical services and
research (stem cell services)
(A) Regulations for the product:
Companies wishing to use Stem Cell
products don't have to go through the earlier
regulatory pathway of the phase I and phase
II clinical trials.(6) Conditional approval
process bypasses the conventional phased
clinical trials before approval and requires
only the preliminary safety studies that show
the efficacy is likely. In a small number of
patients the company can show presumed
efficacy and definite safety after which a
conditional marketing approval is given for
seven years. Most important fact is that
national insurance would now pay for these
therapies. This provision allows for post
market analysis of efficacy and early
availability of promising cell therapy
products.
(B) Regulations for the medical services and
research (stem cell services): (Figure 1)
Here the Japanese regulators divide Stem Cell

Therapy in to the low risk, medium risk and
high risk. Doctors practicing low risk therapy
need permission only from their own
institutional committee. Medium risk
therapies need clearance from a committee
outside the institute and High risk therapies
are very heavily regulated. (7)
To elaborate, risk stratification is performed
on the basis of risk to human life and health,
Class III - Low risk, that is work involving
processing of somatic cells, can be performed
by taking approval from the institutional
certified committee for regenerative medicine
only. Class II - Medium risk therapies need
approval of institutional certified committee
The regulations state that, Cell therapy product
means a medicinal product manufactured through
physical chemical, and/or biological manipulation ,
such as in vitro culture of autologous, allogeneic, or
xenogeneic cells. However, this definition does not
apply to the case where a medical doctor performs
Korean regulations for stem cell therapy:
The Korean guidelines, in their definition of cell
therapy product, exclude cases where a medical
doctor performs minimal manipulation of
autologous or allogeneic cells. (8)
of regenerative medicine as well as an
external special committee for regenerative
medicine. Class I - High risk that is Human
IPCs, ESCs are regulated by a committee for
regenerative medicine within the institute,
special committee for regenerative medicine
and the ministry of health, labor and
welfare.
Since the implementation of these laws, two
new products have been given conditional
marketing approval and over 100 Stem Cell
Therapy centers have opened up in Japan.
Figure 1: Risk stratification and Separate
regulatory oversight for different categories
according to risk stratification

minimal manipulation which does not cause safety
problems of autologous or allogeneic cells in the course
of surgical operation or treatment at a medical center
(simple separation, washing, freezing, thawing, and
other manipulations, while maintaining biological
properties).
Therefore by their regulations treatments done
at a medical center using minimally manipulated
cells are excluded from the regulatory framework
of cell therapy products.
Regulatory framework in Europe:
European medical agency (EMA) has drafted a
separate legislation for regenerative medicine
products which is known as act on advanced
therapy medicinal product (ATMP).(9) Various
regenerative medicine products are put into this
newly designed category for such products. This
legislation recognizes the difference between the
drugs and stem cell products. Another law
formulated by EMA, called Hospital Exemptions
act (HE) allows a practitioner or an institute to
offer stem cell therapy as a form of treatment for
terminally ill patients. (10) The law states that,
Advanced therapy medicinal products which
are prepared on a non-routine basis according
to specific quality standards, and used within the
same Member State in a hospital under the
exclusive professional responsibility of a medical
practitioner, in order to comply with an
individual medical prescription for a custom-
made product for an individual patient, should
be excluded from the scope of this Regulation
whilst at the same time ensuring that relevant
Community rules related to quality and safety
are not undermined.
Recently in the year 2016 EMA also formulated
a PRIority Medicines (PRIME) program to
support development of medicines for unmet
medical needs. (11) Under this scheme promising
therapies and medicines that are important for
public health will be given additional support and
accelerated regulatory approval. The products
that are in the stage before Phase II as well as
Phase III trials can be a part of this scheme.
These schemes highlight patient's right to seek
treatment for a disease that has no cure. If there
is no treatment available, then regulatory bodies
should not prevent patients from taking benefit
of safe but unproven therapies. This concept was
known as compassionate use in Europe earlier
which has now evolved in the legislation
explained above. In Australia and Canada as well
such laws exists which allow marketing and
provision of safe but unproven therapies and
drugs to patients that suffer from incurable
disorders after taking their informed consent and
by reporting any possible adverse events noted.
In Australia this is known as Special access
scheme and in Canada it is known as special
access program. (12,13)
New concepts that have emerged from the recent
regulations (Figure. 2)
1. Conditional marketing approval
2. Risk Stratification
3. Post-Hoc efficacy analysis
4. Presumed efficacy
5. Patients right to seek treatment
6. Distinction between cellular therapies
7. Distinction between a stem cell product and
medical service
8. Non-homologous use
Figure 2: New concepts emerging from the recent
regulations
Conditional approval
Conditional approval first introduced by Japan
and later also implemented by USA is
revolutionary concept that allows for faster
marketing of promising stem cell therapy
products. In the last century the most promising
medical research was done by individual doctors
in their field of practice who kept patient care at
the center of their research. But industrialization
of pharmaceutical sciences and stricter
regulations implemented for getting marketing
approval made it impossible for individual
practitioners to develop promising therapies and
medicines. Conditional approval allows for
promising therapies to be marketed for a
stipulated time at an earlier stage of Phase I or
pilot trials which are sufficient to prove the safety
of the therapy and suggest efficacy of the same.
The concept of conditional approval has shifted
the control of medical innovation back in the

hands of individual doctors practicing and
researching to provide better patient care.
Risk Stratification
Risk stratification means grouping the stem cell
therapies and products based on their risk to
human life and health. Such stratification helps
to differentiate between less harmful and more
harmful cellular therapy products.
A) Using this principle Korea has excluded the
safer forms of therapies from their regulatory
framework.
B) Japanese guidelines have based their
regulatory requirements on risk stratification.
With low risk needing only institutional
clearance, medium risk needing outside
institutional clearenace and high risk
requiring clearance from MHLW.
C) The new proposed American law REGROW
Act, using this principle has proposed more
permissive regulatory pathway for safe cell
therapies such as cells or tissues that are
minimally manipulated for a non-
homologous use; or more-than-minimally
manipulated for a homologous or non-
homologous use, but are not genetically
modified.
Post-Hoc efficacy analysis
Concept of Post-Hoc efficacy analysis means that
true efficacy of the product or therapy can be
determined post marketing. This is the most
dramatic shift in the current medical regulations
that do not permit marketing of unproven drugs
and therapies. However based on this principle
therapy or product can be permitted for
marketing based on studies showing definite
safety but preliminary efficacy analysis. The roots

of this concept are in the basic principle of
compassionate use, facilitating early availability
of potentially lifesaving experimental medication
which are safe but unproven.
This is a revolutionary concept that has already
been implemented in Japan since November 2014
and 2 products have already received approval
under this legislation. Recently, based on this
concept REGROW Act has also been put forth in
the USA.
The basis of post - hoc efficacy analysis lies in the
concept of Practice based evidence which allows
for gathering information regarding efficacy of a
particular therapy after using it clinically as a
form of treatment and recording the clinical
outcomes in the patients treated. Unlike evidence
based medicine, the concept of practice based
evidence gives the flexibility to offer a treatment
after the safety is established and offer it as a
treatment while simultaneously studying the
effects on clinical outcome.
Presumed efficacy
It has been debated earlier that the modern
standards for efficacy testing are too idealistic and
may in turn slow down the progress of medical
science. Although the regulations are for safe
guarding the patients they fail to determine when
a therapy will be considered as proven. The
current regulations ask for Phased clinical trials
that take up to 6 to 8 years before a new product
can come in the market and have a cost estimate
of about 5 million dollars. Current research and
statistical methods are more suited for a drug or
a molecule that has finite chemical reactions in
the body, however in biological products there
are infinite possibilities for interactions and
therefore it may take decades before a conclusive
efficacy analysis can be done.
Japan in their regenerative medicine regulations
for the first time proposed a concept of 'Presumed
efficacy'. This means that the preliminary trials
that lack statistical rigor but are suggestive of
beneficial clinical outcome can be considered as
the evidence for efficacy of the treatment. Simply
put, it means that it can be reasonably assumed
that therapy will be effective in larger population
based on a finding with a smaller population.
It was earlier considered unethical to charge for
therapies that have shown efficacy in smaller
populations. Japan in their recent regulations
allowed for marketing of such therapies under a
conditional approval and these therapies were
also covered under Japan's national health
insurance schemes. In the recently proposed
REGROW act, USA; similar suggestions have
been made for allowing safe therapies to be
marketed based on their presumed efficacy.
Patient's right to seek treatment
Up till the last century availability of the clinical
treatments was solely based on decisions of
regulatory bodies. If a treatment did not fit the
criteria laid out in the regulations then it was not
allowed in the market, thereby denied to the
patients. Although this was to safeguard patients
from adverse effects of under investigated
therapies, terminally ill patients were losing out
on promising therapies due to strict demands for
proving efficacy.
Most of the patients with progressive fatal
disorders do not have enough time for an
experimental drug which has proven safety and
has shown efficacy in smaller trials to be tested
in the statistical rigor of bigger trials. These drugs
could be potentially lifesaving for these patients.
There were many efforts lead by patients and non-
profit organizations, which demanded access to
such experimental drugs for patients with
terminal illnesses.
The origin of compassionate use is in the World
Medical Association's Declaration of Helsinki on
ethical principles for medical research involving
human subjects. The declaration in their clause
on unproven intervention in clinical practice
states that, 'In the treatment of an individual
patient, where proven interventions do not exist
or other known interventions have been
ineffective, the physician, after seeking expert
advice, with informed consent from the patient
or a legally authorised representative, may use
an unproven intervention if in the physician's
judgement it offers hope of saving life, re-
establishing health or alleviating suffering. This
intervention should subsequently be made the
object of research, designed to evaluate its safety
and efficacy. In all cases, new information must
be recorded and, where appropriate, made
publicly available'. (14)

The concept of patient's right to seek treatment
is highlighted in the White paper published by
the International society of Cellular Therapy
which states that Patients seeking medical
treatment for cellular therapies have the
following rights that must be respected by
healthcare providers and all associated with their
care. The right to seek treatment: patients and
their families/partners have the right to seek
treatments for their diseases. No entity should
withhold this fundamental right unless there is a
high probability of harm to the patients.(15)
Efforts made by the patients in accordance with
this ethical principle led to changes in the
legislation for USA, Europe and several other
countries in the world. In USA this was
implemented as Treatment/Emergency IND
initially and later as Right to try Act in 2015. (5)
In Europe this was implemented as
Compassionate use Act and recently a program
was launched to support to development of
priority medicines for unmet medical needs,
PRIME. In addition other Acts like Hospital
Exemption Act in Europe (10), Special access
program in Australia (12) and special access
scheme in Canada (13) are based on this
principle.
These compassionate use programs highlight
patient's right for seeking unproven but safe
experimental drugs and allows access to such
medicines and therapies at the personal
recommendation and responsibility of the treating
physician. Such use is deemed ethical and can
be charged for after receiving an informed
consent from the patient, explaining the possible
adverse effects if any and informing the patient
about the experimental nature of the therapy.
Unfortunately, in India there are no laws or
regulations for compassionate use. Indian
regulators and guideline formulators have not
taken into consideration the right's of these
patients to seek treatments that may potentially
save their lives.
Distinction between different types of
cellular therapies
Earlier the guidelines did not make distinction
between different types of cells, processes of
procurement and routes of administration.
However the recent guidelines have made various
distinctions and have made separate regulations
and guidelines accordingly.
In USA the REGROW Act makes distinction
between minimally manipulated cells and more
than minimally manipulated cells.(2) Minimally
manipulated cells are defined as, cells procured
using technologies when there is no intended
alteration in the biological characteristics of the
cell population relevant to its claimed utility,
performed by a medical doctor at a medical
center during the same surgical procedure
without compromising the safety of the cells; this
may include separation of mononuclear cells,
washing, centrifugation and suspension in
acceptable medium. All the other cell types are
characterized as more than minimally
manipulated cells.
In Japan, there is a separate law designed only
for the classification of the regenerative medicine
products based on their safety profile.(7) These
products are divided into 3 separate classes as,
class I - High risk, Class II - Medium risk and
Class III - Low risk products (Figure).
In European guidelines, the products are divided
into minimally and more than manipulated as
well. Minimal manipulation is defined as cells
procured through simple technologies like cutting,
grinding, shaping, centrifugation, soaking in
antibiotics of antibiotic solutions, sterilization,
irradiation, cell separation, concentration or
purification, filtering, lyophilization, freezing,
cryopreservation and vitrification. However there
are no separate guidelines for the use of these
products as allowed in Japanese and USA laws.
Distinction between a cellular therapy
product and cellular therapy medical service
Advent of cellular therapy has given rise to a huge
dilemma for regulators whether to regulate these
as a product or a medical service. Therefore most
of the guidelines are too restrictive where it is
considered as a product or too liberal where it is
considered a therapy. Although burden of
evidence lies on both therapy and product; the
criteria for marketing approval have been
traditionally very different for both. Every new
product is regulated separately and the evidence
for one is usually not applicable to the other

therefore companies designing different products
need to seek different approvals. The guidelines
for these are also very strict. However a therapy
once proven safe and effective can be used by
multiple practitioners and they individually do
not need to seek approval for the same. This is a
basic distinction in the product and therapy
which most of the guidelines in the world
including Indian guidelines fail to understand.
Japanese guidelines however have been very
progressive and they have designed 2 separate
laws for products and therapies. These two laws
have also been very progressive in their field of
application allowing fast track conditional
approval for products and mandatory approval
from MHLW only for high risk therapies. USA
has taken a step ahead in not only allowing a
fast track conditional approval for products but
also allowing different companies to get faster
marketing approval based on exhibited
biosimilarity with an already existing approved
product.
Non-homologous use
The proposed REGROW Act 2016 has for the first
time made a provision for conditional approval
of therapies and products using minimally and
more than minimally manipulated cells for non-
homologous use i.e. not in the same body system
as that of the source of the cells. (2)
Current Indian Scenario:
In sharp contrast to this, in India the latest
guidelines made by Indian council of Medical
Research (ICMR) in 2013 are moving backward
and are in the process of trying to implement
policies that will completely destroy the stem cell
therapy field in India.(16) The Major problem is
that the ICMR does not seem to understand that
there is a difference between a product and a
medical service. They refuse to accept that there
is something like stem cell 'therapy'.
The regulations were quiet progressive in their
earlier versions (2002 and 2006) allowing co-
existence of research and therapy based on the
risk stratification of cells.(17) In addition to
already existing institutional oversight by
Institutional Ethics Committee (IEC), ICMR
added another layer of oversight at an
institutional level called Institutional committee
of stem cell research and therapy (IC - SCRT) and
at a national level called National Apex
Committee for stem cell research and therapy
(NAC - SCRT). Indian innovators and doctors
have collected a huge amount of clinical evidence
in this field and are ahead of doctors from any
other country in the world. Since 2002 there are
a total of 80 published clinical studies from India
in various different neurological, musculoskeletal
and cardiovascular disorders which is amongst
the largest published clinical evidence from a
single country. Most of these disorders are
incurable and fatal. All of these publications
unanimously document the safety of cellular
therapy and potential benefits. All of this
development was led by individual doctors and
practitioners who innovated the stem cell
therapies for incurable disorders keeping the
patient at the center of their research. This is
becoming increasingly difficult now since the
evolution of latest ICMR and CDSCO guidelines.
As time progressed the guidelines regressed from
liberal guidelines that were permissive of cellular
therapies in India to the most recent restrictive
guidelines that suggest all stem cell related work
can only be performed as research. These
restrictive policies are completely destroying the
field of stem cell therapy in India. A peculiar thing
to note is that by changing the guidelines the
progress of the field of stem cell therapy in India
is now controlled by the corporate who have large
funds. Current policies of ICMR which insist on
having an IC-SCR registered with NAC-SCRT,
registration with CTRI, having a data safety
monitoring board and a DCG(I) license for GMP
facility means that only heavily funded private
corporates can fulfill their criteria. The current
policy ensures that government/ semi
government institutions, smaller private hospitals
and individual doctors can never fulfill their
criteria. Even if institutions want to work in
accordance with ICMR regulations, NAC-SCRT
makes it extremely difficult for them to even begin
the process. This is evidenced by the fact that out
of 107 institutes that have applied for NAC-
SCRT registration only 24 i.e 22% have actually
got the NAC-SCRT registration. Also the process
is extremely long and can take several months to
years to complete. The result of this is a real life
example in recent months wherein a semi

government hospital in Gujarat doing wonderful
limb salvage stem cell therapy free of cost was
made to stop their work whereas a private
corporate was given permission to charge patients
(US $2200) for similar type of indication. Any
regulatory policy that favors only those who can
spend large amounts of money and discourages
or prevents those who cannot spend large
amounts of money is not in the national interest
of our country.
Indian regulators fail to understand the 1]
distinction between drug and stem cell therapy
2] distinction between stem cell therapy product
and stem cell therapy. The current Indian
guidelines do not incorporate any of the new
concepts that have emerged in the recent
progressive guidelines of other countries.
Proposed changes in the Indian regulations:
We would like to propose a road map for
regulating stem cell work in India in such a
manner that the safer forms of therapies are easily
available to patients with incurable diseases
whereas less safer forms of therapies are
regulated more strictly.
(A) For this we propose that there should be 3
different sets of guidelines for,
1) Researchers - Those who are doing basic
laboratory research and clinical trials in
patients.
2) Corporate Manufacturers - companies
that are manufacturing stem cells and
stem cell related products on a large
scale
3) Clinical stem cell therapists - doctors and
institutes that offer cellular therapy as
a treatment.
Separate rules and regulations should be
formulated for these. The researchers should
follow ICMR guidelines. Corporate
manufacturers should follow CDSCO / DCG(I)
guidelines.
Clinical stem cell therapies should further be
categorized into
Low risk: Therapies using autologous and
minimally manipulated stem cells. These
therapies could be permitted under the oversight
from the IEC.
Medium risk: Therapies using more than
minimally manipulated allogeneic cells of non-
embryonic origin. These therapies would need
oversight of IEC and approval from CDSCO/
DCG(I).
High risk: Embryonic/ Fetal stem cells and
iPSCs. Therapies using these cells would require
oversight of IEC and approval from CDSCO and
ICMR.
A key aspect of debate between clinicians and
regulatory bodies is what new clinical indications
should be considered as approved to offer stem
cell therapy. We believe that if there are
publications, that document safety and presumed
efficacy of stem cell therapy in a particular
indication from any part of the world, then this
should be considered as an accepted indication.
(B) The membership of NAC-SCRT should be
expanded to include more members from the
clinical side having experience and expertise
in Stem cell therapy so that a more balanced
view is taken. The Chairmanship of NAC-
SCRT should be changed by rotation every
year so that fresh insights are available to
the committee.
Conclusion:
We conclude that the Ministry of Health along
with ICMR and CDSCO need to study the
REGROW Act of USA as well as the Japanese
and Korean legislations for regenerative medicine
and come up with a definitive set of regulations
which are permissive of medical practitioners
offering safer forms of cellular therapies like
autologous and minimally manipulated therapies
and stricter regulations for more unsafe cellular
therapies and corporate producing and selling
stem cells as a product. The Indian guidelines
should also incorporate principles of risk
stratification, post-hoc efficacy analysis,
conditional marketing approval, distinction
between stem cell therapies and stem cell
products and patients right to seek treatment.
This will result in only safe treatments being
available as therapy and at the same time ensure
that patients suffering from serious medical
conditions are not deprived of stem cell therapies
that can help them.

Reference:
1. Sharma AK, Sane H, Gokulchandran N, Paranjape
AA, Kulkarni P, Badhe PB The need to review the
existing guidelines and proposed regulations for
stem cell therapy in India based on published sci-
entific facts, patient requirements, national priori-
ties and global trends. Indian Journal of stem cell
therapy. 2015 June;1(1):7-20.
2. Bill presented in American senate, committee on
health, education, labor and pensions (2016), Reli-
able and Effective Growth for Regenerative Health
Options that Improve Wellness act, REGROW act,
available from https://ec.europa.eu/futurium/
en/system/files/ged/REGROW_act_usa.pdf, last
accessed on 8/6/2016.
3. TheUnitedStatesofAmerica,DepartmentofHealth
and Human Services, Code of Federal Regulations,
Food and Drug Administration, Part 1271: Regula-
tions for Human cells, Tissues, and Cellular and
Tissue based products. Available from: http://
www.accessdata.fda.gov/scripts/cdrh/cfdocs/
cfcfr/cfrsearch.cfm?cfrpart=1271showfr=1. Ac-
cessed: 8th June 2016.
Food and Drug Administration, chapter 6A, Pub-
lic Health Safety Act; available online at https://
www.law.cornell.edu/uscode/text/42/chapter-
6A. Last accessed online on 8/6/2016
Food and Drug Administration, H.R.3012, Right to
try Act; available online at https://
www.congress.gov/bill/114th-congress/house-
bill/3012. Last accessed online on 8/6/2016
6. Amendment of the pharmaceuticals affairs law.
Availablefrom:http://www.mhlw.go.jp/english/
policy/health-medical/pharmaceuticals/dl/
150407-01.pdf last accessed on 8/6/2016
7. Institutional framework for promoting implemen-
tation of regenerative medicine, Ministry of Health
and Welfare Japan. Available from: http://
www.mhlw.go.jp/english/policy/health-medi-
cal/medical-care/dl/150407-01.pdf. Last accessed
on 8/6/2016.
8. Regulations on review and authorization of bio-
logical products 2010.10, Korea Food and Drug
Administration. Available from: https://
www.google.com / url?sa=trct=j q= esrc=s
source=web cd=1 cad=rjauact=8
v e d = 0 C B 4 Q F j A A a h U K E w j Y l N 2 i t a b
HAhWVj44KHTnDBNE url=http%3A%
2F%2Fwww .mfds.go.kr %2Fjsp% 2Fcommon%
2Fdownfil e.jsp% 3Ffileinfo% 3D%2Ffiles%
2Fupload%2 F1% 2FTB_F_IN FODATA% 2F92
18%2F71d5a5a567f74eaa45 86e4b8144a5824.pd f
ei=W73MVZj7BZW fugS5hpOIDQ usg
=AFQjCNHZ4zF WcRlH0IV-mxSUJtnY1Er35Q
sig2=1jJTSpxuqquz KdFv539xNA bvm=bv.
99804247, d.c2E.Accessed: 8/6/2016.
9. European medical agency, Advance therapy medi-
cal products act. Available online at http://
www.ema.europa.eu/ema/index.jsp?curl=pages/
regulation/general/general_content_000296.jsp,
last accessed on 8/6/2016.
ec.europa.eu/health/files/advtherapies/
2013_05_pc_atmp/07_2_pc_atmp_2013.pdf last
accessed on 8/6/2016
www.ema.europa.eu / ema/index.jsp%3
Fcurl%3Dpages / regulation/general/
general_content_000660 .jsp%26mid%3DWC
0b01ac 058096f643 last accessed on 8/6/2016
12. Department of health of Australia, therapeutic
goods administration, available online at https://
www.tga.gov.au/form/special-access-scheme last
accessed on 8/6/2016
13. Health Canada, Special access program, available
online at http://www.hc-sc.gc.ca/dhp-mps/
acces/drugs-drogues/index-eng.php last accessed
on 8/6/2016
14. World Medical Association. (2013). World Medi-
cal Association Declaration of Helsinki: ethical
principles for medical research involving human
subjects. JAMA: the journal of the American Medi-
cal Association; 310(20), 2191.
15. Gunter KC, Caplan AL, Mason C, Salzman R,
Janssen WE, Nichols K Horwitz E. Cell therapy
medicaltourism:timeforaction.Cytotherapy.2010;
12(8):965-968.
16. National guidelines for stem cell research, Indian
council of Medical Research, Department of Health
and Dept. of Biotechnology, 2013. Available online
on http://www.icmr.nic.in/guidelines/NGSCR
202013.pdf, last accessed on 8/6/2016
17. Guidelinesforstemcellresearchandtherapy,Dept.
of Biotechnology and Indian Council of Medical
Research, 2007. Available online on http://
w w w . i c m r . n i c . i n / s t e m _ c e l l /
stem_cell_guidelines_2007.pdf, last accessed on 8/
6/2016.

As part of my post-doctoral research work, in
October 2013 I moved to India with the intent to
explore, understand, and map out the stem cell
terrain in India. Immensely excited, becauseboth
in academic literature and mainstream media,
stem cell research and therapies were being
heralded as either dystopian nightmares come
alive or utopic potential for perpetual health
finally realized. I then entered this fray to find
out which of these scenarios was the reality (or
close to the reality), particularly in India. In the
two years since I have been here, in and out of
clinics, hospitals, research labs, offices, and policy
meetings, I have found that the reality of stem
cells in India lies somewhere in between these
two extremes -that there are problems, but also
some promissory potential to this research
therapy. I have seen near miraculous recoveries
for debilitating diseases but also seen the
disappointment when the results of a particular
treatment do not meet the expectations.
In this short article , I want to first acknowledge
my debt to the large number of people who have
given me access to their processes, their
involvement with stem cells, their offices, their
labs, their hospitals, their clinics, their patients,
and above all their time and conversations. When
talking to the different sets of people involved
with stem cell research and therapy, I often
thought of them as stakeholders, because there
was so much at stake for them, both materially
and immaterially. The expectations of patients,
the need of physicians to provide cures for their
suffering patients, the policy makers drive to
ensure safety and efficacy of treatments for
patients at ethically viable costs, the intent of
researchers to be the first and best with particular
protocols all combined to create an alive, vibrant,
and engaged public (which I call stakeholders).
In this article, I talk like an anthropologist and
not a scientist, with the aim to make clear to my
scientist colleagues (reading this article) about
how I have thought through some of the ideas
they have shared with me. Further, I wish to
move my work away from any firm rigid stance,
which claims stem cells as the absolute solution
to all/any medical conditions and on the other
side stay away from claims that this amazing
work is nothing but snake oil cure and empty
promises. In order to arrive at a nuanced reading
of India's stem cell terrain, I offer up a chance to
read the different stakeholders ideas, aspirations,
opinions around the issue of ethnics and
regulations. In particular, I look at the responses
tothe two documents written in 2013 by the
Ministry of Health (MoH henceforth). The first is
a draft guideline issued in Feb 2014 by the Central
Drugs Standard Control Organization (CDSCO)
of the Ministry of Health, Government of India
called Guidance Document for Regulatory
Approvals of Stem Cell and Cell Based Products
(SCCPs). The other was issued by the Indian
Council Of Medical Research (ICMR henceforth)
and is the 2013 Stem Cell Research Guidelines.
Below I call these guidance document and
ICMR guidelines respectively.
Ethnography of Stakeholders:
While there are more stakeholders in the stem
cell therapy field than the two major groups I
addresses below (i.e. physicians and policy
makers), I had to limit my analysis due to
constraints of space and time. And any imagined
binaries that might emerge between physicians
and policy makers, are just that - imagined. The
stem cell terrain in India is indeed very complex
with multiple stakeholders (with new
complexities and stakeholders emerging
everyday), so the focus here on two groups is just
the start of a conversation rather than an attempt
to polemical boundaries.
Physicians (clinicians, therapists, and
researchers)
Keeping that in mind, I should make clear that
there are various kinds of physicians operating
Stem Cell terrains in India: An Anthropologist explores
Nayantara Sheoran, Ph.D., M.Sc.
Department of Anthropology and Sociology of Development
Corresponding Address: Graduate Institute of International and Development Studies.
Geneva 21 - Switzerland. Email: nayantara.sheoran@graduateinstitute.ch

within the Indian milieu when it comes to stem
cell therapeutics and some laboratory work. That
is physicians in private or public hospitals,
physicians with training in neurosurgery to those
with training in gynecology, physicians from
rural, urban, or urban peripheral spaces,
etc.Interestingly, of all the physicians I worked
with, the physicians that are the most ethical and
often working at facilities that aim for holistic
healing ask for the ICMR regulations to be slightly
loosened. While this may benefit them to a small
extent, the true winners some argued, in such a
scenario will be physicians that are not working
within the same ethical or moral parameters as
the leading group of physicians. As one leading
physician of stem cell therapeutics, Dr. Singh
explained to me, the focus of the State to curtail
medical research and therapeuticinterventions in
the stem cell terrain was misguided as it focused
on practitioners that were intent on making a
positive difference in patient treatments. He felt
that the State should work on promoting stem
cell research and therapies amongst the larger
population, rather than constantly focusingon a
few problematic practitioners.
Dr. Singh in his conversations made clear to me
that the benefits to the nation and the patient
outweigh the risks that may be inherent in the
nascent science. What was impressive about the
hospital where he worked and performed most
of the stem cell transfers and therapies was one
of the better private hospitals I had seen in India.
It was not part of a corporate chain of hospitals,
but rather a stand-alone hospital where extreme
attention was paid to inform and take consent
from their patients. They followed each and every
rule in the ICMR documents and took additional
steps to meet internationally established criteria
by the US FDA for stem cell research and
therapeutics. Once the new ICMR guidelines
and guidance documents were released, the
hospital took that voluntary stance and started
performing stem cell therapies (transfers) with
minimally manipulated cells (i.e. bone marrow
extraction and cell separation with minimal
manipulation) rather than established cell lines
or MSCs.
While the above hospital voluntarily participated
in protocols that not only met, but also exceeded
the ICMR guideline expectations some others
did not do so. For example, the CSDCO
guidance document ask physicians to follow a
particular protocol for transfer of stem cells (this
is in the case where the physicians were working
with cells purchased from a lab). It asks that the
physician conduct tests on thawed cells by at least
following three of these criteria:
• Tests of viability, cell identity, and function
should be repeated after thawing and/or
expansion.
• The yield of viable cells and of quantitative
functional equivalents should be compared
to those values before freezing.
• Sterility should be confirmed
(Pg 24, Guidance Document for Regulatory
Approvals of Stem Cell and Cell Based Products)
However, one of the physicians I observed did
not follow these protocols. This is a physician I
worked with who has results that are stellar in
terms of self-reported and physician observed
improvements. Not one of his patients who I
spoke with (I spoke with four of his patients) was
dissatisfied with the results. I was in and out of
this physicians' space and observed his
consultations with patients, his operation room
extraction procedures, and transfusions. The
processes were quite unlike the ones I observed
in the hospital in Mumbai, but rather informal,
the consent form quite casually administered, and
he operated along with his nurse.
While some could deem his practices problematic
and perhaps unethical, his stellar results for a very
nominal charge to patients with limited resources
would lead others to deem him an ethical
practitioner of stem cell therapeutics. As he
explained to me, he had limited resources, but
was determined to help patients that came to
him. As a medical practitioner, he felt it was his
ethical obligation to share with patient
alltreatment modalities as options for the patients
(and their families to choose from). He continued
further, on the question of experimental nature
of these particular therapies
What you and the international establishment see
as experimental and perhaps unethical, my
patients seek out as their only hope. The ICMR
and the government want to curb therapeutics,
but encourage research on stem cell. For them, it

is ethical to sit and see people suffer everyday,
just so long as they do not upset some
international granting organization or the FDA.
(Paraphrased from conversations with the
physician working with stem cell therapies)
For him, he was on the forefront of an ethical
battle and it involved curing and providing hope
to his patients. Since the issuance of the
guidance document and ICMR guidelines, he
had stopped taking any fees for his therapies, but
rather started enrolling his patients in what he
deemed self-funded clinical trials.
Clearly, it becomes important to recognize the
need for one set of physicians, which I could
easily dub good versus others who operate by
a different brand of everyday practices as 'bad;'
however, that reading would be too reductive.
For even the physicians who's practices of medical
delivery I found a bit outside my comfort zone,
had stellar results with their patients. For their
patients, they were 'good' as they were able to
provide them cures and ability to partake in
activities that were outside their imaginable realm
before treatments.So while some followed the
guidelines and others did not, they all operated
within a rather opaque ethical space that they
justified with individual ethos and practices. The
government issued documents had curbed the
way they practiced stem cell therapeutics, but this
they viewed as limiting the ability of medicine
and science to develop in India.
Policy Makers
On the other hand of the ethical debate were the
policy makers, who while cognizant of these same
opaque ethical spaces in India, worked towards
situating Indian stem cell research and
therapeutics on an international platform of
respectability and recognition. This was a goal
quite similar to those of the physicians, who also
wanted India to be the forerunner in this nascent
medical innovation. Of course, while the end
points were the same, the relationship the policy
makers had with the physicians was quite a
contentious one. The two main problems that
were identified by the policy makers in regards
to stem cell therapies were the fact that some
physicians were providing 'unproved' medical
treatments at very high costs and that there were
no safeguards in place for patients who might
not benefit or worse still suffer from negative
consequences of these experimental therapies.
As was pointed out to me by one of the former
members of the regulatory bodies, what the ICMR
and the Ministry were doing was for the benefit
of the science itself.
See, nobody understands this, but every
regulation that is put in place is not to restrict
science, but to protect and enhance it. When these
policies are put in place, it is not to punish 'bad'
medical practitioners, but to prevent the 'good'
ones from getting a bad name because of the
others. If not controlled now, and if India gets a
bad reputation for providing dangerous
treatments, then nobody…not one single doctor
will benefit (sic). We are trying to protect the field
of stem cells by putting regulations in place and
use international ethics as our guiding principals.
We want India to be a place for the best medical
treatments, both for Indian and non-Indian
patients.
(Paraphrase from conversation with former
policy advocate)
For her, safeguards against hucksters of stem cell
therapies today prevented the entire Indian
medical community and medical tourism
enterprise suffering in the future. Again, a risks
and benefits analysis formed the framework,
where the risks needed to be minimized in the
short term to ensure long-term benefits.
This conversation was held alongside other
conversations about protecting the financial
wellbeing of 'poor' patients who were desperate
for a cure; but at no point was the issue raised of
providing this form of personalized medicine at
government hospitals or government subsidized
prices. Even though some preliminary work
(following some of the most stringent
international standards of ethics and medical
development) was ongoing in government
institutions in India, the large focus of the policy
makers was on the private stem cell clinics,
hospitals, and institutions. The focus remained
on enhancing these spaces by encouraging
them to operate within internationally
established norms, rather then focusing on
enabling the government sponsored stem cell to
excel in order to provide personalized medicine

to the largest portion of India. The 'poor' within
this framework were available as docile
experimental bodies, but never viewed as worthy
citizens deserving top tier medical care from their
government medical establishment.
Conclusion
When I started my fieldwork, the physicians were
quite disturbed by the regulatory bodies'
continuous disruption to the scientific and
therapeutic stem cell research spaces in India.
However, by 2015, I have witnesses a number of
collaborations, supported by the State in private
clinics with the aim to promote stem cell science;
however, within certain parameters. I have also
seen private hospitals, clinics, and physicians
offering to work within the ICMR guidelines that
allow for minimally manipulated cells, just so long
as they can provide cures for their patients. As I
start the process of analyzing two years of data
collected, the one reality that becomes
overwhelmingly clear is that there are is perhaps
no absolute utopia or dystopia when it comes to
stem cell research and therapy, but rather a much
more fluid space that is viewed as dystopic or
utopic by different sets of people based on their
subjective positions vis-à-vis stem cells.
Funding Disclosure
Reflections in this article emerge from a larger
research project supported by the European
Research Council (ERC), Grant Number 313769.

Introduction
The healthcare sector is now not just limited to
the concept of organ replacement but has shifted
to the concept of organ regeneration and cell
based therapies have played an important role
in this paradigm shift. Cell based therapies are
based on the application of stem cells which are
differentiating and immunomodulatory.
Avascular necrosis is a condition that occurs due
to disruption of blood supply to the bone which
ultimately leads to collapse of the bone. The
conventional treatment of AVN may be non-
operative and/or operative. Non surgical
treatment modalities include elimination of
causative factors, use of anti-osteoporotic agents
(bisphosphonates etc), analgesics, non-weight
bearing exercises etc. Operative treatment
includes core decompression, joint preservation
and replacement (total or partial) procedures.
However, the results of the aforementioned
treatment modalities have been unsatisfactory.
The extent and the location of the lesion involving
the femoral head determines the prognosis of
A novel cell based treatment for Avascular Necrosis of
femoral head: A case report
Dr. Pradeep V. Mahajan1*, Prabhu Mishra, Anurag Bandre, Dr. Swetha Subramanian,
Dr. Manu Menon, Dr Neetin Desai2*
1* Chairman and Managing Director, StemRx Bioscience Solutions Pvt. Ltd.
Corresponding Author and Address: Dr. Pradeep V. Mahajan, StemRx Bioscience Solutions Pvt. Ltd.,
R-831,T.T.C., Thane Belapur Road, Rabale, Navi Mumbai, Maharashtra, India
Email: drpvmahajan@gmail.com
2*Corresponding Author and Address2 : Dr.Neetin S. Desai, Amity University,
Mumbai, Maharashtra, India
Email: neetindesai@gmail.com
Abstract:
Avascular necrosis (AVN) of the femoral head is a progressive disease characterized by a vascular
insult to the blood supply of the femoral head, which can lead to collapse of the femoral head and
subsequent degenerative changes. The femoral head, carpals, humerus are the most commonly
affected bones. Regenerative medicine - a branch of translational research, uses cell based therapies
in tissue engineering which deals with the process of re-engineering or regenerating human cells,
tissues or organs at the defective sites to restore or establish normal function. On the basis of the
concept of regenerating cells we present a case that deals with the treatment of avascular necrosis
of femoral head in a 35 year old male patient with cell based therapy.
Keywords : Regenerative Medicine, AVN, Mesenchymal Stem Cells, Cytokines
AVN. Ohzono et al. reported that the lesions
involving the lateral one third of the weight
bearing area or diffuse femoral head involvement
had more than 90% chance of collapse [1]. Lee
etal.stated that the overall collapse rate of AVN
(hips) was 78% within 2 years [2]. In a case study
on AVN of the hip joint, Steinberg et al. reported
that 92% of cases progressed to collapse when
managed with non-operative treatment [3].
The use of autologous stem cells has shown
promise in halting the progression of AVN of the
femoral head, and subsequently preventing
young patients from undergoing total hip
arthroplasty[4]. Animal experiments have
demonstrated the potential of stem cells to
promote neovascularization which effectively
increase the blood perfusion in an anoxic
environment and thus inhibit further necrosis of
tissues [4,5]. Thus, transplantation of
mesenchymal stem cells may be a minimally
invasive strategy for the treatment of femoral
head necrosis.
In 2002, Hernigou and Beaujean first described

a technique for injecting mesenchymal stem cells
combined with standard core decompression to
introduce biologics into an area of necrosis[6].
This study was done in 116 patients using
autologous mesenchymal stem cells and in 5
years clinical follow up, promising results were
observed for the patients of grade II AVN where
the progression of the disease was stopped [7].
Thus, transplantation of mesenchymal stem cells
may be a minimally invasive strategy for the
treatment of femoral head necrosis.
In this case report, we describe the treatment of
avascular necrosis of the femoral head with bone
marrow and platelet concentrate.
Case report:
A 35 year old male patient came to our hospital
with complaint of pain in left hip joint since 10
years. The patient had intermittent pain radiating
to his right groin and antero-medial thigh region.
He also complained of restricted hip movements
with stiffness and mild pain in the lower back.
History revealed that the patient had a fall from
stairs 15 years ago. No other relevant medical/
surgical history was reported by the patient. The
patient had consulted an orthopedic surgeon
who prescribed painkillers and nutritional
supplements. However, relief from symptoms
was minimal and temporary.
On the patient's first visit to our hospital,
complete clinical, hematological and radiological
investigations were done. Clinical scoring of the
patients' condition was done based on Harris Hip
Score. A total score of 28 (poor) was calculated
based on range of motion scores and the findings
of marked pain, moderate limp, use of 2 canes/
crutches, ability to sit on a high chair for 30
minutes, inability to put on shoes/socks and enter
public transportation.
Table 1: Degree of movement, showing the range
of motion values:
FLEXION: 40 degrees
ABDUCTION: 10 degrees
ADDUCTION: 10 degrees
EXT. ROTATION: 5 degrees
INT. ROTATION: 8 Degree
Radiological investigations [X-ray (Fig 1 and MRI
Fig 2] revealed:
• Marrow oedema in left femoral head, left
acetabulum,
• Small erosions in the acetabulum and
femoral articular margins,
• Thinning of articular cartilage and reduction
in joint space with synovial thickening.
A.P. view of pelvis with both hip joints reveal
that left femoral head shows cortical irregularity
of articular surface with gross narrowing of left
hip joint space. The neck and the cortical head
structure is maintained inspite of irregular erosion
as described earlier. Osteopenia is visualized.
Above findings are suggestive of AVN of left
femoral head.
Figure 1: XRAY of both hip joints showing AVN
affected femoral head area (circled) dated 03-02-2014
Figure 2: MRI of the hip joint confirming AVN of the
femoral head dated 03-02-2014

Based on the assessment a final diagnosis of
Avascular necrosis of the left femoral head (Stage
II as per FICAT and ARLET classification) was
confirmed.
Material and Methods
On the basis of clinical findings the patient was
admitted for treatment in March 2014 and a
personalized treatment protocol was made based
on the severity of the condition and general
factors such as age of the patient, body mass
index etc. The protocol involved harvesting bone
marrow concentrate, stromal vascular fraction
(SVF) from adipose tissue and platelet rich plasma
(PRP) from peripheral blood.
Bone marrow concentrate contains mixed
population of progenitor cells comprising of
mesenchymal and hematopoietic cells along with
mononuclear cells. Stromal vascular fraction
isolated from adipose tissue consists of endothelial
cells, adipocyte progenitors, immune cells,
fibroblasts, pericytes and stromal cells. Platelet
rich plasma is a platelet concentrate and a
reservoir of cytokines and growth factors.
Vascular endothelial growth factor (VEGF),
fibroblast growth factor (FGF), platelet derived
growth factor (PDGF), transforming growth
factor (TGF-?), insulin-like growth factor (IGF)
and epidermal growth factor (EGF) that are
present in PRP play an important role in the
healing process. Transplantation dose was
calculated on the basis of cell count and grade of
the disease. Transplantation was done intra
articularly using fine needle decompression.
Results:
Following treatment, the patient was kept under
observation for 48 hours at the hospital. This was
a non-interventional period for homing of the
cells and for monitoring the general condition of
the patient. The patient was advised non weight
bearing physiotherapy exercises (passive) such as
stretching of the hamstrings, hip flexors and
abductors followed by range of motion exercises
for the hip and knee. Strengthening exercises
were gradually instructed to strengthen primarily
the quadriceps, hip abductors and hamstrings
musculature. The patient was instructed to
continue the rehabilitation exercise program for
1 year.
Follow-up was done periodically wherein clinical
and radiological assessment was done. The
patient showed gradual improvement in clinical
parameters of pain and movements. Harris hip
score calculation was done at the 3rd, 6th and
12th month follow-up. At the end of the first year,
the score was 89 (good). The patient was free of
pain 6 months after treatment. The patient is now
able to walk unlimited distances without using
cane/crutches, can sit comfortably on any chair
and is able to enter public transportation.
Clinical Impression of the result
A.P view of pelvis with both hip joints reveals
right hip joint normal and left hip showing
improvement in joint space (circled area)
compared to the pretreatment X-ray. The cortical
irregularity of the articular surface of the femoral
head shows improvement. Osteopenia is
visualized.
Impression: Reduction in cortical irregularity
noted.
Figure 3: One year post operative X-ray of the hip
joints dated 05/03/2015
Discussion:
The common causes implicated in the etiology of
avascular necrosis of bone are corticosteroid use
and trauma which results in interruption of blood
supply to the area thus leading to necrosis of the
bone. The other causes of AVN may be systemic
lupus erythematosus (SLE), pancreatitis,
alcoholism, gout, radiation, sickle cell disease and
infiltrative diseases (e.g. Gaucher's disease).
The occurrence of AVN among younger adults,

use of prosthesis and risk of surgery limit the
application of conventional treatment modalities
such as arthroplasty, core decompression etc. Cell
based therapy is thus gaining popularity as a
non/minimally invasive therapeutic modality in
the treatment of various disorders. The unique
properties of stem cells namely differentiation
potential, self renewal, anti-inflammation and
immune-modulation aid in regeneration of
structures/tissues rather than repair which
commonly occurs after conventional/surgical
treatment modalities.
In our study, the cause of AVN was traumatic
injury, which possibly remained undetected in
the initial phase. After undergoing cell based
therapy, the patient showed gradual
improvement with each follow-up which
reaffirms the positive effect of cell based therapy
in cases of avascular necrosis of femoral head.
Homing of stem cells is a complicated process
which involves an array of molecules. Necrosis
of cells induces the release of a series of signaling
molecules, in which specific receptors or ligands
expressed in injured tissues play an important
role. Vascular endothelial cells express a variety
of adhesion molecules. Stem cells are capable of
adhering to these endothelial cells and reach the
site of ischemia. Studies have shown that
mesenchymal stem cells can not only migrate into
the femoral head, but also remain in the region
for a relatively long time.
The route of administration of cells also plays an
important role in the degree of improvement
achieved. In our study, the patient was
administered intra-articular and intravenous
doses of mesenchymal stem cells. In a study by
Zhang-Hua Li et al., intravenous administration
of cells resulted in directional migration of the
cells to femoral heads to survive in the necrotic
environment. The rationale behind intra-articular
administration was to achieve higher
concentration of cells in the localized area.
Nevertheless, further studies should be done to
study the directional migration of stem cells in
order to formulate more specific treatment
protocols.
Conclusion
This case report highlights the positive outcome
of cellular therapy achieved in a patient with
avascular necrosis of the femoral head. The
patient withstood the process fairly well with no
obvious complications or adverse reactions. The
results are being maintained (after 1 year) and
has also resulted in an improvement in the overall
quality of life of the patient.
References :
1. Ohzono K, Saito M, Sugano N, Takaoka K, Ono K.
The fate of nontraumatic avascular necrosis of the
femoral head. A radiologic classification to formu-
late prognosis. ClinOrthopRelat Res 1992; 277 :
73-8.
2. Lee MS, Chang YH, Chao EK, Shih CH. Conditions
before collapse of the contralateral hip in osteone-
crosis of the femoral head. Chang Gung Med J
2002;25:228-37.
3. Steinberg ME, Hayken GD, Steinberg DR. The con-
servative management of avascular necrosis of the
femoral head. In: Arlet J, Ficat PR, Hungerford DS,
eds. Bone circulation. Baltimore: Williams and
Wilkins, 1984:334-7.
4. Tateishi-Yuyama E, Matsubara H, Murohara T, et
al. Therapeutic angiogenesis for patients with limb
ischaemia by autologous transplantation of bone-
marrow cells: a pilot study and a randomised con-
trolled trial. Lancet. 2002 Aug 10;360(9331):427-35
5. Ikenaga S, Hamano K, Nishida M, et al. Autolo-
gous bone marrow implantation induced angio-
genesis and improved deteriorated exercise capac-
ity in a rat ischemic hindlimb model. J Surg Res.
2001,96(2):277-283
6. Herndon JH, Aufranc OE. Avascular necrosis of
the femoral head in the adult. A review of its inci-
dence in a variety of conditions. ClinOrthopRelat
Res. 1972;86:43-62.
7. Hernigou P, Beaujean F. Treatment of osteonecro-
sis with autologous bone marrow grafting.
ClinOrthopRelat Res. 2002;405:14-23.

Introduction:
Osteoarthritis of the knee is the most common
form of arthritis that cause pain, stiffness and one
of the leading causes of disability among adults
[1,2]. The pathogenesis of knee OA has been
linked to biomechanical and biochemical changes
in joint cartilage, e.g. inability to withstand
normal mechanical stresses, limited nutrients and
oxygen supply, inadequate synthesis of
extracellular matrix components, increased
synthesis of proteinases and overall apoptosis of
chondrocytes [3-6].
Current treatments for knee OA achieve poor
clinical results and fail to modify cartilage. Joint
replacement is the last treatment option, bearing
enormous effort and expenses [7, 8].
Mesenchymal Stromal Cells (MSC) opened new
therapeutic perspectives provided their
regenerative potential and ability to modulate
inflammation [9-12]. MSCs constitute a
heterogeneous population of cells, in terms of
their morphology, physiology, and expression of
surface antigens. The Mesenchymal and Tissue
Stem Cell Committee of the International Society
for Cellular Therapy has proposed criteria
necessary to define human MSC's. First, MSCs
must be plastic-adherent when maintained in
standard culture conditions. Second, MSCs must
express CD105, CD73, and CD90, and lack
expression of CD45, CD34, CD14 or CD11b,
CD79a or CD19, and HLA-DR surface molecules.
Third, MSCs must differentiate into osteoblasts,
adipocytes, and chondroblasts in vitro [13]. Many
studies show co-cultured MSC to induce
chondrocyte proliferation and extracellular
matrix protein synthesis, including aggrecan and
type II collagen [14,15]. The capacity to
differentiate into cells of the chondrogenic lineage
and produce extracellular matrix together with
their proven anti-inflammatory potential brought
to focus bone marrow MSC as a potential
treatment for osteoarthitis. The European Union
(EU) Regulation on advanced therapies
considered expanded MSC a medicinal product
[16,17].
Direct intra-articular injection of MSCs would
offer great advantages if it could be translated
Treatment of Knee Osteoarthritis with Autologous Bone
Marrow Derived Mesenchymal Stem Cells : A case report
Rohit Kulkarni 1*, Abhijit Bopardikar1, M. Dhanasekaran1
1. Reelabs Pvt Ltd, 1st Floor, KK Chambers, Sir P.T. Road, Fort, Mumbai - 400 001
Corresponding Author and Address: Dr. Rohit Kulkarni, Reelabs Pvt Ltd,
1st Floor, KK Chambers, Sir P.T. Road, Fort, Mumbai - 400 001. Email: rrk@reelabs.com
Abstract:
Osteoarthritis is one of the most common diseases, and it affects 12% of the population around
the world. Although the disease is chronic, it significantly reduces the patient's quality of life. At
present, stem cell therapy is considered to be an efficient approach for treating this condition.
Current available treatments focus on addressing symptoms and joint replacement is the last
treatment option. Autologous Bone marrow Derived Mesenchymal stem cells show the most
potential for stem cell therapy of osteoarthritis. Advanced therapies with mesenchymal stem cells
build new expectations to improve the results of OA treatments. BMMSC applied in animal
models, show encouraging results in modulating inflammation and joint cartilage repair. Several
studies applied autologous mesenchymal stem cells to treat knee osteoarthritis in humans by
means of an intra-articular injection. In our study autologous bone marrow expanded mesenchymal
cells were injected intra-articularly in patient affected with knee osteoarthritis. After 6 months of
follow-up we observed significant clinical outcomes with no adverse events.
Keywords: Osteoarthritis, stem cell therapy, Autologous, Bone marrow, Mesenchymal stem
cells, intra-articular

into clinical practice as it would avoid surgeries
and associated side effects, such as hypertrophy
and ossification of periosteal coverage, immune
reaction and disease transmission caused by
xenograft coverage. More importantly, simplicity
and ease of the injection could provide better
treatment opportunities, especially for the elderly
with comorbidity. The safety and the efficacy of
intra-articular injection of Bone marrow derived
MSCs (BM MSCs) in patients with knee
osteoarthritis.
Case Report:
A 56-year-old female presented with a history of
3-4 years of knee joint pain on legs. She was
unable to walk more than a mile without
significant pain. Pain was severe with stiffness
of the knee joint and instability, and had forced
the patient to discontinue running. The patient
had received a recommendation for joint
replacement. Pain occurred during climbing or
descending stairs and with standing or walking
for two hours. Pain interrupted sleep and limited
participation in regular activities. We collected
100ml of Bone marrow sample from the patient
as per standard operation procedures of the
ReeLabs Private Limited stem cell laboratory.
Mononuclear cells were isolated from bone
marrow aspirate by density gradient
centrifugation using Ficoll PaqueTM.
Erythrocytes present in the cell fraction were
lysed using 0.7 % NH4Cl solution for 5 min at
room temperature. The cells were subjected to
further centrifugation and the pellet recovered
was resuspended in PBS. Single cell suspension
was further enumerated and evaluated for its cell
viability using Trypan Blue staining. Cells were
plated at a density of 4 X104/cm2 in T-25 flasks
and cultured in DMEM-LG and supplemented
with 10 % FBS and 1 % antibiotic-antimycotic
solution. The cells were maintained for 2-4 days
before first medium change. Standard culture
conditions of 370C, 5 % CO2 and 95 % humidity
were maintained and 70-80 % confluency was
obtained. The primary culture was sub cultured
until passage 3.
The releasing criteria of stem cells included cell
viability (95%), free from bacterial and viral
contamination, absence of endotoxin and
immunophenotyping showing expression of
CD90, CD105, and CD 73 was more than 90%.
For each treatment, a total of 30 × 106 Bone
marrow derived mesenchymal stem cells in 1 ml
solution were administered intra-articular
injection one dose per month over three months.
During the treatment period, the patient had one
episode of temporary fever without needing an
additional treatment. No other medical treatment
except rehabilitation training was performed. The
patient was followed up for 6 months since the
last transplantation. In our patient, significant
improvement was observed regarding most of the
clinical aspects, such as, less knee pain, ease in
walking and sitting, reduction in stiffness of the
joint, reduction in swelling and relative ease in
climbing stairs. Symptoms before and after bone
marrow derived mesenchymal stem cells
treatments were carefully compared (Table 1).
Table 1: Symptoms before and after therapy:
Before therapy After therapy
Pain in knee Less Pain
Difficulty in walking Ease in walking and
and sitting sitting
Stiffness of the knee Reduction in Stiffness
joint of the joint
Occasional swelling Reduction in swelling
Difficulty in climbing Relative ease in climbing
stairs stairs
Discussion:
Osteoarthritis is a major public health problem
which causes pain and disability in one third of
all affected patients. It is one of the crucial
musculoskeletal disorders characterized by the
imbalanced homoeostasis and destruction of the
articular cartilage, in which pro-inflammatory
cytokines are important catabolic regulators
during OA cascade [18]. Cellular based therapy
is a promising strategy for osteoarthritis
treatment. Studies have reported on the safety
and outcome of using bone marrow-derived
MSCs for treating osteoarthritis [19,20]
A few case reports in human also described
encouraging early clinical outcomes of intra-
articular injection of bone marrow MSCs. In line
with previous experimental studies and clinical
case reports, this study demonstrated a great

promise of intra-articular injection of AD MSCs
with details of clinical, radiological, arthroscopic,
and histological results. Current medical
treatment for osteoarthritis are commonly
associated with gastrointestinal, hepatic, renal,
or cardiac side effects [21], and surgery is
inevitably invasive no matter how minimal it is.
This makes intra-articular injection a valuable
option, especially in the elderly. Considering very
low incidence of infection, 0.002% [22], and
feasibility of the procedure, intra-articular
injection of MSCs would be a valuable therapy
for osteoarthritis if evidences accumulate. MSCs
are known to home and are preferentially
attracted to diseased tissue rather than to intact
tissue [23-25]. Using this homing ability, some
authors demonstrated that intra-articularly
injected MSCs attached to cartilage defect,
proliferated, and participated in regeneration of
articular cartilage [26,27], decreased synovial
fluid concentration of prostaglandin E2, and
retard the progression of osteoarthritis [28,29] .
Jo et al. treated 18 patients with intra-articular
injection of autologous adipose tissue derived
MSC for knee OA. They divided patients in 3
groups, administrating 10×106, 50×106 and
100×106 MSC. The outcomes showed intra-
articular knee injection of 100×10e6 autologous
MSC improved function and pain as well as
cartilage defects by regeneration of hyaline-like
articular cartilage [30]. Wong et al. reported a
prospective, randomized clinical trial in 56
patients. They injected cultured bone marrow-
derived mesenchymal stem cells into varus knees
with cartilage defects after performing high tibial
osteotomy and microfracture procedures. They
concluded that an intra-articular injection of
cultured MSCs is effective in improving both
short-term clinical and MOCART outcomes in
patients undergoing HTO and microfracture for
varus knees with cartilage defects [31]. Wakitani
et al. reported the first stem cell study for the
treatment of knee OA in humans. They aspirated
bone marrow blood from both sides of the iliac
crest. After approximately 20 days of cell culture,
they embedded the stem cells in collagen gel
which was produced from porcine tendon. They
performed high tibial osteotomies (HTO) in 24
patients with medial compartmental knee OA.
They found that the cartilage defects were
covered with hyaline cartilage-like tissue in the
cell-transplanted group. However, in this study,
the clinical improvement was not significantly
different [32]. In our patient also, intra-articular
injection of bone marrow derived mesenchymal
stem cells showed significant improvement
regarding most of the clinical aspects.
Conclusion:
In summary, intra-articular injection of BM
MSC's into the osteoarthritic knee improved
function and pain of the knee joint without
causing adverse events. Although further studies
with more patients need to be performed to
confirm the above results, this study suggests that
our treatment is a promising minimally invasive
therapy for osteoarthritis patients.
References
1. Lawrence RC, Felson DT, Helmick CG et al. Esti-
mates of the prevalence of arthritis, other rheumatic
conditions in the United States. Part II. Arthritis
Rheum 2008; 58:26-35.
2. Dillon CF, Rasch EK, Gu Q et al. Prevalence of knee
osteoarthritis in the United States: Arthritis data
from the Third National Health and Nutrition Ex-
amination Survey 1991-94. J Rheumatol
2006;33:2271-2279.
3. Michael JW, Schlüter-Brust KU, Eysel P . The epi-
demiology, etiology, diagnosis and treatment of
osteoarthritis of the knee. Dtsch Arztebl Int
2010;107: 152-162.
4. Bijlsma JW, Berenbaum F, Lafeber FP . Osteoarthri-
tis: An update with relevance for clinical practice.
Lancet 2011;377: 2115-2126.
5. Lories RJ, Luyten FP . The bone-cartilage unit in
osteoarthritis. Nat Rev Rheumatol 2011;7: 43-49.
6. Heinegard D, Saxne T .The role of the cartilage
matrix in osteoarthritis. Nat Rev Rheumatol 2011;7:
50-56.
7. AmericanAcademyofOrthroapedicSurgeryTreat-
ment of osteoarthritis of the kenn (non-arthro-
plasty). Full guideline. Rosemont, IL: American
Academy of Orthropaedic Surgeons. 2008.
8. Hochberg MC, Altman RD, April KT, Benkhalti M,
Guyatt G, et al. American College Rheumatology
2012 recommendations for the use of
nonpharmacologic and pharmacologic therapies
in osteoarthritis of the hand, hip and knee. Arthri-
tis Care Res (Hoboken) 2012;64: 465.
9. Uth K, Trifonov D .Stem cell application for
ostearthritis in the knee joint: A minireview. Word
J Stem Cells2014; 6: 629-636.

10. Baghaban EM, Malakooty PE . Mesenchymal stem
cells as a potent cell source for articular cartilage
regeneration. World J Stem Cells 2014;6: 344-354.
11. Gupta PK, Das AK, Chullikana A, Majumdar AS .
Mesenchymal stem cells for cartilage repair in
ostheoartritis. Stem Cell Res Ther 2012; 3: 25.
12. Matsumoto T, Okabe T, Ikawa T, Iida T, Yasuda H,
et al. Articular cartilage repair with autologous
bone marrow mesenchymal cells. J Cell Physiol
2010;225: 291.
13. Dominici M, Le Blanc K, Mueller I, Slaper-
Cortenbach I, Marini F, Krause D, et al. Minimal
criteria for defining multipotent mesenchymal stro-
mal cells. The International Society for Cellular
Therapy position statement. Cytotherapy 2006; 8:
315-7.
14. Acharya C, Adesida A, Zajac P, Mumme M, Riesle
J, et al. Enhanced chondrocyte proliferation and
mesenchymal stromal cells chondrogenesis in
coculture pellets mediate improved cartilage for-
mation. J Cell Physiol,2012; 227: 88.
15. Wu L, Prins HJ, Helder MN . Trophic effects of mes-
enchymal stem cells in chondrocyte co-cultures are
independent of culture conditions and cell sources.
Tissue Eng Part A, 2012;18: 1542.
16. Commission Directive 2009/120/EC of 14 Septem-
ber 2009. Amending Directive 2001/83/EC of the
European Parliament and of the Council on the
Communitycoderelatingtomedicinalproductsfor
human use as regards advanced therapy medici-
nal products .
17. Orozco L, Soler R, Morera C, Alberca M, Sánchez
A, et al. Intervertebral disc repair by autologous
mesenchymal bone marrow cells: a pilot study.
Transplantation.2011.
18. Monteforte P, Sessarego P, Rovetta G. Sonographic
assessment of soft tissue alterations in osteoarthri-
tis of the knee. Ital Med Lav Erg 2008;30:75-7.
19. Orozco L, Munar A, Soler R, Alberca M, Soler F,
Huguet M, et al. Treatment of knee osteoarthritis
with autologous mesenchymal stem cells: a pilot
study. Transplantation 2013; 95: 1535-41.
20. Orozco L, Munar A, Soler R, Alberca M, Soler F,
Huguet M, et al. Treatment of knee osteoarthritis
with autologous mesenchymal stem cells: two-year
follow-up results. Transplantation 2014; 97: e66-8.
21. Singh JA. Stem cells and other innovative intra-ar-
ticular therapies for osteoarthritis: What does the
future hold? BMC Med 2012;10:44.
22. Bellamy N, Campbell J, Robinson V et al.
Intraarticular corticosteroid for treatment of os-
teoarthritisoftheknee.CochraneDatabaseSystRev
2006:CD005328.
23. Agung M, Ochi M, Yanada S et al. Mobilization of
bone marrow-derived mesenchymal stem cells into
the injured tissues after intraarticular injection and
their contribution to tissue regeneration. Knee Surg
Sports Traumatol Arthrosc 2006;14:1307-1314.
24. Sordi V. Mesenchymal stem cell homing capacity.
Transplantation 2009;87:S42- S45.
25. van Buul GM, Kotek G, Wielopolski PA et al. Clini-
cally translatable cell tracking and quantification
byMRIincartilagerepairusingsuperparamagnetic
iron oxides. Plos One 2011;6:e17001.
26. Mokbel AN, El Tookhy OS, Shamaa AA et al. Hom-
ing and reparative effect of intraarticular injection
of autologous mesenchymal stem cells in osteoar-
thritic animal model. Bmc Musculoskelet Disord
2011;12:259.
27. Lee KB, Hui JH, Song IC et al. Injectable mesenchy-
mal stem cell therapy for large cartilage defects-A
porcine model. Stem Cells 2007;25:2964-2971.
28. Murphy JM, Fink DJ, Hunziker EB et al. Stem cell
therapy in a caprine model of osteoarthritis. Ar-
thritis Rheum 2003;48:3464- 3474.
29. Al Faqeh H, Nor Hamdan BM, Chen HC et al. The
potential of intra-articular injection of chondro-
genic-induced bone marrow stem cells to retard the
progression of osteoarthritis in a sheep model. Exp
Gerontol 2012;47: 458-464.
30. Peeters CM, Leijs MJ, Reijman M, van Osch GJ, Bos
PK .Safety of intraarticular cell-therapy with cul-
ture-expanded stem cells in humans: a systematic
literature review. Osteoarthritis Cartilage 2013-21:
1465.
31. Wong KL, Lee KB, Tai BC, Law P, Lee EH, Hui JH.
Injectableculturedbonemarrow-derivedmesenchy-
mal stem cells in varus knees with cartilage defects
undergoing high tibial osteotomy: a prospective,
randomized controlled clinical trial with 2 years'
follow-up. Arthroscopy 2013; 29: 2020-8.
32. Wakitani S, Imoto K, Yamamoto T, Saito M, Murata
N, Yoneda M. Human autologous culture ex-
panded bone marrow mesenchymal cell transplan-
tation for repair of cartilage defects in osteoarthritic
knees. Osteoarthritis Cartilage 2002; 10: 199-206.

Scsi journal april 2016 final volume 2

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