STEM CELLS AS

REGENERATIVE
MEDICINES
STEM CELLS AS REGENERATIVE MEDICINES

Cell therapy, more specifically stem cell therapy, holds significant promise in the treatment of
various diseases. Stem cells address a great therapeutic approach for tissue engineering in
particular, as they are known to differentiate into various tissue lineages, including bone, carti-
lage, cardiac muscle, and even into the cells of the central nervous system. Another great
strength of the stem cells is that autologous cell transplantation is available and the patients can
be treated with their own cells. This greatly reduces the risk of host immune-related problems,
and further enables more patient-friendly and patient-specific therapy.

STEM CELL THERAPIES FOR INDICATIONS:

Orthopedic: Avascular Necrosis, Non-union bone fracture, Knee Osteoarthritis

Neurological: Spinal Cord Injury, Autism, Cerebral Palsy, and Multiple Sclerosis

Vascular: Acute myocardial infarction (AMI), Peripheral arterial disease (PAD)

1. USE OF STEM CELLS IN ORTHOPEDICS

A) Stem cells for the treatment of avascular necrosis

Avascular necrosis (AVN) also known as osteonecrosis, is defined as cellular death of bone com-
ponents due to interruption of the blood supply, the bone structures then collapse, resulting in
bone destruction, pain, and loss of joint function. AVN usually involves the epiphysis of long
bones, such as the femoral and humeral heads and the femoral condyles, but small bones can
also be affected. In clinical practice, AVN is most commonly encountered in the hip. Depending
on the amount of femoral head involved, collapse of the articular surface will occur as the
disease advances.

Avascular necrosis of the femoral head is a debilitating disease of multifactorial genesis,

predominately affects young patients, and often leads to development of the secondary osteo-
arthritis.

In terms of cellular biology, AVNFH is related to the loss of equilibrium between osteoblast and
osteoclast formation. The osteoclast formation process is stronger than osteoblast formation.
Therefore, a part of bone can be destroyed, leading to damage at the femoral head. This disequi-
librium is related to a reduction in the osteogenic differentiation capacity of bone marrow mes-
enchymal stem cells (BMMSCs). Such a reduced osteogenic differentiation capacity can lead to
reduced local microcirculation that also results in ischemia. Therefore, in addition to symptomat-
ic treatment of AVNFH, current AVNFH treatment should (1) stimulate BMMSC proliferation and
differentiation into bone cells to compensate for necrotic bone cells and (2) stimulate angiogen-
esis or vasculogenesis to supply enough blood to the femoral head to stop the necrosis.

The evolving field of regenerative medicine offers promising treatment strategies using bone
marrow cells, biomaterial scaffolds, and bioactive factors, which might improve clinical outcome.
Early stages of AVN with preserved structural integrity of the subchondral plate are accessible to
retrograde surgical procedures, such as core decompression to reduce the intraosseous pressure
and to induce bone remodeling. In contrast, advanced stages of AVN with collapsed subchon-
dral bone require an osteochondral reconstruction to preserve the physiological joint function.
Several studies, both clinical and pre-clinical, have demonstrated the efficacy of stem cells for
the treatment of AVN of the FH. Intraosseous injection protocol involving BMC and biomaterial
for the treatment of early stages of AVN of FH thereby serve as a point-of-care therapeutic
option

B) Treatment of non-union bone fracture using stem cell therapy

Fractures are common and most people will experience at least one during their lifetime. Bone
has a remarkable property to self-repair following injury and is usually a rapid and efficient
process. Most bone fractures heal with the modern medical and surgical care without any com-
plication, however the healing process can be compromised in certain clinical circumstances. An
estimated 5% to 10% of the fractures either delay repair (delayed union) or do not heal
(non-union) with conventional treatment. Although this figure is not homogenous and may vary
depending on the type of fracture, ranging from up to 18.5% in the tibia diaphysis to 1.7% in the
femoral shaft. The healing of fractures is a complex physiological process which could be inter-
rupted by various factors and non-union fractures are a serious complication. Thus, develop-
ment of novel therapeutic methods to treat non-union and delayed union fractures’ becomes a
clinical necessity. There is growing interest in the use of bone marrow derived stem and progeni-
tor cells for bone repair. Increasing evidence now indicates that physiological bone remodelling
occurs in close proximity to blood vessels and that these vessels carry perivascular stem cells
that differentiate into osteoblasts. Traditional strategies rely on the patient’s own stem and
progenitor cells present at site or in circulation for bone regeneration, which could be a chal-
lenge if those cells are missing. Therefore, alternative cell based therapies using autologous
bone marrow concentrate are being explored for the treatment of delayed union and non-union
fractures.

C) Stem cells help in filling gaps between bones

For many patients the removal of several centimetres of bone from the lower leg following a
serious injury or a tumour extraction is only the beginning of a long-lasting ordeal. Autologous
stem cells have been found to accelerate and boost the healing process. Literature has shown
that without stem cells, it takes on average 49 days for one centimetre of bone to regrow; with
stem cells, that period has been reduced to 37 days.

Surgical intervention of several spinal disorders entails decompression of the spinal cord and
nerves which can lead to subsequent biomechanical instability of the spine. Spinal arthrodesis
(fusion) is often required to correct this instability and necessary to eliminate the resulting
pathological motion of vertebral segments. Therefore, the achievement of proper spinal fusion is
a critical determinant of treatment efficacy. During spinal fusion procedures, bone grafts are
placed to promote bone healing and to provide stability. Clinical studies have demonstrated
that when osteo-progenitor cells present in bone marrow concentrate are combined with
osteo-conductive materials, fusion rates are comparable to autograft results.

D) Stem cells for Knee Osteoarthritis

Knee osteoarthritis (OA) is a chronic degenerative disorder which could be distinguished by

erosion of articular cartilage, pain, stiffness, and crepitus. Not only aging-associated alterations
but also the metabolic factors such as hyperglycemia, dyslipidemia, and obesity affect articular
tissues and may initiate or exacerbate the OA. The poor self-healing ability of articular cartilage
due to limited regeneration in chondrocytes further adversely affects the osteoarthritic microen-
vironment. Traditional and current surgical treatment procedures for OA are limited and incapa-
ble to reverse the damage of articular cartilage. To overcome these limitations, cell-based thera-
pies are currently being employed to repair and regenerate the structure and function of articu-
lar tissues.

Various clinical studies have reported promising results for using BMC in treating cartilage
pathology. Bone marrow stem cells serves as a source of growth factors that are thought to play
an important role as a result of their anabolic and anti-inflammatory effects. Autologous bone
marrow concentrate (aBMC) represents the next generation of injectable intra-articular orthobi-
ologic therapy for patients with cartilage disease. Similar to many PRP systems, bone marrow
concentrate (BMC) is generated through density-gradient centrifugation of bone marrow aspi-
rate (BMA). As a third-generation orthobiologic, BMC has an advantage over PRP in that it con-
tains a greater concentration of bone-marrow–derived mesenchymal stem cells (BMMSCs),
which have demonstrated benefit in facilitating the regeneration of articular cartilage.

2. Stem cells in the treatment for neurological disorders

New research shows that transplanted stem cells migrate to the damaged areas and assume the
function of neurons, holding out the promise of therapies for Alzheimer’s disease, Parkinson’s,
Spinal Cord Injury, Stroke, Cerebral Palsy, Battens Disease and other neurodegenerative diseases.
A) Stem cells for spinal cord injuries (SCI)

SCI is a devastating disorder afflicting millions across the world. Presently, there is no cure or
effective standard of care for SCI. Cellular therapy provides a means of restoring the cells lost to
the injury and could potentially promote functional recovery after such injuries. Human bone
marrow (BM) cells have ability to differentiate into the mature neurons or glial cells. Autologous
BM derived stem cells are very effective in the treatment of acute spinal cord injury patients.
BMSCs possess angiogenic properties. It is hypothesized that improved blood flow and oxygen
supply within the injury area may have contributed to the functional improvements seen in SCI
patients transplanted with autologous bone marrow derived stem cells.

B) Cerebral Palsy

Cerebral palsy is a broad term that refers to a group of neurological disorders caused by an
injury to the brain that affect body movement and muscle coordination. There is currently no
cure for cerebral palsy and no standard therapy that works for all patients. Cord blood stem cells
are able to differentiate into neural cell types. This research also lends support for the pioneering
clinical work at Duke University, focused on evaluating the impact of autologous cord blood
infusions in children diagnosed with cerebral palsy. Dr. Joanne Kurtzberg, a professor of pediat-
rics and pathology and director of Duke's Pediatric Blood and Marrow Transplant Program, is
infusing the child's cord blood stem cells back into the body in an effort to facilitate repair of
brain tissue damaged by perinatal hypoxic (oxygen-deprived) events. To date, more than 20
children have participated in the experimental treatment.

C) Multiple Sclerosis

Multiple sclerosis (MS) is a multifocal inflammatory disease of the Central Nervous System (CNS)
in which the fatty myelin sheath around the axons of the brain and spinal cord are damaged,
leading to demyelination and scarring. There is a broad spectrum of signs and symptoms of
multiple sclerosis affecting young individuals which cause paralysis of the limbs, and sensation,
visual and sphincter problems. Adult bone marrow derived cells were shown to induce similar
immunomodulatory and neuro-regenerative effects and thus induce neuroprotection.

Stem cells or progenitor cells can reach the Central Nervous System either following intrathecal
transplantation or through the blood stream. Stem cells express a set of adhesion molecules and
chemokine receptors on its surface. When such cells are injected into the circulation they leave
the blood stream and migrate into different tissues, including the central nervous system.
Cell-based therapies provide a newer strategy for bolstering regeneration and repair through
neuro-axonal protection or remyelination.
3. Use of stem cell therapy in vascular disorders:

A) For Acute Myocardial Infarction (AMI):

Coronary heart disease and chronic heart failure are common diseases and have an increasing
frequency. Although re-vascularisation strategies and pharmaceutical therapies are able to delay
ventricular remodeling, till date no therapeutic strategy is available that might prevent or even
reverse this process of remodelling and consequent ventricular failure. Chronic coronary artery
disease and heart failure impair quality of life and are associated with subsequent worsening of
the cardiac pump function. Numerous studies carried out in the past few years have demon-
strated, that the stem cell therapy has been considered as a safe therapeutic procedure in heart
diseases, especially in cases of destroyed and/or compromised heart muscles.
Several preclinical as well as clinical trials have shown that transplantation of autologous bone
marrow cells or precursor cells improved cardiac function after heart attack and in chronic coro-
nary heart disease. The period of infarction seems to be irrelevant to regenerative potency of
stem cells, since stem cells therapy in old infarctions (many years old) is almost equally effective
in comparison to recent infarcts. Today the therapeutic strategy of cell administration during
cardiac surgery or coronary artery intervention is adapted in the clinical practice.

Injecting specialized cardiac stem cells, into a heart attacked patient's heart rebuilds healthy
cardiac tissue. Several studies have demonstrated that stem cell therapy reduces scarring and
regenerates healthy tissue, now it is found that the stem cell technique boosts production of
existing adult heart cells (cardiomyocytes) and spurs recruitment of existing stem cells that
mature into heart cells. The current mechanism on the effect of stem cell therapy is found to be
indirect by stimulating the proliferation of dormant surviving host heart tissue, and it attracts
stem cells already in the heart. The resultant new heart muscle is functional and durable, but the
transplanted stem cells themselves do not last long. Consistent with previous studies, the
researchers found that the heart's native stem cells are not responsible for the normal replenish-
ment of lost heart cells, but they do contribute in rebuilding damaged heart tissue after heart
attack. This study shows that existing heart cells contribute to formation of new heart cells in the
normal heart through a gradual cycling process, dying heart cells are replaced by new ones.
Further, these effects can be amplified through stem cell therapy. We are conducting a random-
ized placebo controlled, multi centre study in AMI (Acute Myocardial Infarction) patients treated
with autologous bone marrow derived stem cells and assessing the safety and efficacy of these
stem cells in restoring the normal heart function.

B) Use of stem cells in peripheral artery disease (PAD) e.g. critical limb ischemia

The scientific literatures are available on the therapeutic potential of autologous adult stem cells
derived from bone marrow. PAD (Peripheral Arterial Disease) is a chronic disease that
progressively restricts blood flow causing poor blood circulation (generally in the legs) and if left
untreated can lead to serious medical complications, including heart attack, stroke, amputation
and death. Many people can manage the symptoms of PAD and stop its progression through
lifestyle changes. If lifestyle changes are not enough, additional medical treatment may be
needed, including prescribed medicine to prevent blood clots, lower blood pressure, cholesterol
level and control pain.

Interventional radiologists treat severe cases of PAD with minimally invasive treatments, includ-
ing angioplasty and insertion of stents. However, some patients have extensive disease with so
many blood vessels affected that they're difficult to treat. In our pilot study at Fortis Escorts
Hospital, New Delhi, a total no. of 17 patients have received the procedure wherein 13 of the
patients avoided major amputation through restored blood flow that eliminated their constant
pain and healed their ulcerations. This is a cutting-edge technology that could benefit millions
of patients suffering with PAD. During the procedure, surgeons extracted specialized stem cells
from the patient's hip, separated them by centrifuge spinning and injected them into the mus-
cles at the site of the blockage to grow new collateral blood vessels that could restore circula-
tion. The outcome has been nothing sort of a miracle to the patients who had non-healing
ulcers in leg and previously lost toe/s due to poor circulation are now feeling like a normal
people again and leading good life. Without this procedure, most of the patients would have
been in a wheelchair. The minimally invasive, point of care technology procedures typically took
less than an hour and required overnight hospital stay. Bone marrow stem cells, which have the
ability to renew and regenerate themselves, have opened the door to treat PAD.

4. Stem cell therapy in Oncology:

Hematopoietic cell transplantation (HCT), also commonly referred to as bone marrow (BM)
transplantation, was first performed successfully 40 years ago. Currently, 50,000 patients per
year receive HCT typically to treat malignant diseases such as leukemia, lymphoma, or multiple
myeloma, and there is now approximately 11 million human leukocyte antigen (HLA)-typed
donors in international donor registries.

Hematopoietic stem cell transplant using human leukocyte antigen (HLA)-matched sibling or
unrelated bone marrow, or related or unrelated cord blood has been performed successfully to
treat patients with different types of hematological malignancies, genetic disorders and heredi-
tary immune deficiencies.

Over 20,000 new patients every year are diagnosed with a lethal disease that is curable with a
bone marrow transplant. One-third has a relative (usually a brother or sister) that matches their
tissue type (HLA) and can donate bone marrow.

Chemotherapy and radiation therapy generally affect cells that divide rapidly. They are used to
treat cancer because cancer cells divide more often than most healthy cells. However, because
bone marrow cells also divide frequently, high-dose treatments can severely damage or destroy
the patient’s bone marrow. Without healthy bone marrow, the patient is no longer able to make
the blood cells needed to carry oxygen, fight infection, and prevent bleeding. BMT replaces stem
cells destroyed by treatment. The healthy, transplanted stem cells can restore the bone marrow’s
ability to produce the blood cells the patient needs.

BMT is most commonly used in the treatment of leukemia and lymphoma. They are most effec-
tive when the leukemia or lymphoma is in remission (the signs and symptoms of cancer have
disappeared). BMT and PBSCT are also used to treat other cancers such as neuroblastoma (can-
cer that arises in immature nerve cells and affects mostly infants and children) and multiple
myeloma. Researchers are evaluating BMT in clinical trials (research studies) for the treatment of
various types of can