Nuffield Health, The Grosvenor Hospital Chester, UK 27 June 2013. GP and Physiotherapy Seminar: Autologous Stem Cell Therapies in Orthopaedics. Moderator and Presenter: Vladimir Bobic, Chester Knee Clinic

2. Autologous MSC
(Mesenchymal Stem Cells) in
Orthopaedics
Vladimir Bobic
Chester Knee Clinic
Nuffield Health,The Grosvenor Hospital and Chester Knee Clinic
Educational Seminar, Chester 27th June 2013

3. From Chondral Damage to Advanced OA:
... to Advanced Medial OA?From Small MFC Chondral Lesion ...

4. Osteochondral Repair and OA: Current Treatment Options
ACI BioPoly
TKR
OATS
Microfracture
Chondroplasty

5. The Subchondral Unit: A New Frontier
re-drawn from Imhof et al. 1999
Henning Madry, Saarland University, Homburg/Saar, Germany
Imhof H, Breitenseher M, Kainberger F, Rand T, Trattnig S. (1999): Importance of subchondral
bone to articular cartilage in health and disease. Top Magn Reson Imaging 10:180–192

6. Articular Cartilage Regeneration
• Regenerated cartilage can be derived from various cell types,
including chondrocytes, pluripotent stem cells, and
mesenchymal stem cells.
• Common scaffolding materials include proteins, carbohydrates,
synthetic materials, and composite polymers.
• Scaffolds may be woven, spun into nanofibers, or configured as
hydrogels.
• Chondrogenesis may be enhanced with the application of
chondroinductive growth factors.
• Bioreactors are being developed to enhance nutrient delivery
and provide mechanical stimulation to tissue-engineered
cartilage ex vivo.

8. |
In what areas do you see stem cell therapy being applied
in orthopaedics and musculoskeletal medicine in this
decade?
*OTE200 members were able to select more than one answer.
200
n=37
Soft tissue healing
New bone growth
Cartilage repair
Osteomyelitis treatment
Spinal cord injury
Osteochondral defects
I do not think stem cell
therapy will be widely used
0 5 10 15 20
18
19
18
2
15
16
10
Number of responses*
58 | MARCH 2013 | Healio.com/Orthopaedics

9. What are Mesenchymal Stem Cells?
•Mesenchymal stem cells are multipotent stromal cells that can
differentiate into a variety of cell types including chondrocytes
and osteoblasts.
•There are several types of stem cells:
•Embryonic stem cells, which differentiate into any cell type,
•Peripotent cells, which can also differentiate into any cell type
except for extra-embryonic tissue,
•Induced pluripotent stem cells, which come from patients and are
manipulated in the laboratory to become pluripotent cells,
•Multipotent progenitor cells, which can differentiate into limited
tissue types.

10. What are Mesenchymal Stem Cells?
!
• Adult stem cells can help
regenerate many tissues
• The best source is the
autologous tissue
• Many different tissues can be
used to process biologically
powerful stem cells
• It seems that the best tissue to
extract MSC is SVF (stromal
vascular fraction) adipose
tissue, which is the best source of
cells and regenerative factors

11. The Telegraph, Sunday 14 April 2013

13. In adults, stem cells act as a repair system for
the body. They allow replacement of ageing
and damaged cells in organs.
In adults, damaged tissue is usually replaced
with scar tissue which loses most of its original
function. Stem cell therapy has the potential to
restore the original structure and function of
the damaged tissue.
Researchers believe that stem cell therapy could
dramatically improve medical treatment, espe-
cially in the field of regenerative medicine.
Adult Stem Cells
KLSMC STEM CELLS
Stem Cells
KUALA LUMPUR SPORTS
MEDICINE CENTRE
INFORMATION FOR
PATIENTS
7th Floor, Wisma Perintis,
47 Jalan Dungun, Damansara Heights,
50490 Kuala Lumpur, Malaysia.
Tel: +603 2096 1033
Fax: +603 2096 1500
Stem Cell Enquiry: +603 2089 5239
E-mail: enquiry@klsmc.com
Website: www.klsmc.com
Outpatient Clinic Hours
Monday to Friday ( 9am to 5pm )
Saturday ( 9am to 1pm )
KUALA LUMPUR SPORTS MEDICINE CENTRE
Location Map
Parking is available in the basementP

16. Saw et al.:Arthroscopy 2013

18. Chondrogenesis: Contained Lesion

19. Chondrogenesis: Uncontained Lesion

20. Saw et al.:Arthroscopy 2011
Gradual Regeneration of Articular Surface

21. •Adipose tissue derived MSCs
•Stem cells isolated from fat are being considered as an option for
treating tissue damage and diseases because of their accessibility and
lack of rejection.
•New research published in BioMed Central's open access journal Stem Cell
Research & Therapy shows that this is not as straightforward as previously
believed, and that fat-derived stem cells secrete VEGF (Vascular Endothelial
Growth Factor) and other factors, which can inhibit cartilage regeneration.
•However pre-treating the cells with antibodies against VEGF and growing them
in nutrients specifically designed to promote chondrocytes can neutralize these
effects.
The Best Source of
Autologous Stem Cells?

22. SVF Adipose Tissue MSCs

28. MSC Clinical Trials: IMPACT
•Currently, UMC Utrecht (Holland) researchers are conducting
the first human trial of an instant mesenchymal stem cell
(MSC) product for use with ACI in what they call the IMPACT
study. In treating focal articular knee cartilage lesions in that
study, the investigators will assess the safety and feasibility of
the MSC construct.
•“In one surgical procedure, we will use the patient’s own
cartilage and mix it with bone marrow from the stem
cell bank,” Saris said. “You use bone-derived stem cells that
can still become whatever they want and you use
chondrocytes that you do not have to culture.
•“We are capable of doing this within one surgical procedure,
which means that you get rid of all the logistics and the costs
of culturing” he said. “This is the next frontier in cell therapy.”

29. MSC Clinical Trials: Cartistem
•Rush University Medical Center in Chicago is conducting the nation's first clinical study
of an innovative stem cell drug, Cartistem, to repair knee cartilage damaged by aging,
trauma or degenerative diseases such as osteoarthritis.
•Cartistem is manufactured from mesenchymal stem cells derived from
allogeneic (donor) umbilical cord blood. Umbilical cord blood is a readily accessible
source of high-quality stem cells, is associated with minimal health risks and carries
relatively few ethical concerns. The stem cells are mixed with hyaluronan, a natural
polymer that plays a major role in wound healing and is a building block of joint
cartilage.
•Cartistem is surgically administered into the area of cartilage damage
following an arthroscopic surgery as an adjunct to microfracture, a commonly
used technique used to repair cartilage damage.The principal investigator on the
study is Dr. Brian Cole, a professor in the department of orthopedics and anatomy and
cell biology at Rush University Medical Center. Dr. Cole is the head of Rush's Cartilage
Restoration Center and is also the head team physician for the Chicago Bulls. Cole and
his co-researchers will assess the drug's safety as well as its ability to regenerate
cartilage repair tissue and reduce pain in patients with localized cartilage loss in the
knee.

30. Summary
Treating cartilage damage can be problematic
because the tissue does not contain blood vessels or
nerves and therefore has a limited ability to re-grow.
Various treatments for cartilage degeneration, such
as drug therapy, arthroscopy and joint replacement,
yield mixed results and are unable to regenerate
damaged tissue.
Finding a biological solution for cartilage regeneration
is one of the fastest growing areas of research and
development in orthopaedics and regenerative
medicine in general.

31. Dr Scarrietta & myStem
Guest Speaker:
Dr Fabio Valerio Sciarretta is Head of Department of
Orthopeadic Surgery at Mercede Clinic, Rome, Italy.
He is a specialist knee surgeon and arthroscopist, whose
special interests are articular cartilage repair in the knee
and the ankle, ligament reconstruction, meniscal repair/
transplantation and minimally-invasive knee replacement.
Dr Sciarretta is a member of numerous national and
international orthopaedic associations, the editor of italian
editions of numerous american and international
textbooks and has published over 50 articles.

32. Autologous
Osteochondral Grafting
and Bone Marrow
Aspirate
Vladimir Bobic
Chester Knee Clinic

33. JBJSA March 1974

34. The Structure of Subchondral Bone
Redrawn from: Imhof H, Breitenseher M, Kainberger F, Rand T, Trattnig S. (1999): Importance of subchondral bone to
articular cartilage in health and disease. Top Magn Reson Imaging 10:180–192
A surprisingly high number of arterial and venous vessels, as well
as nerves, can be seen in the subchondral region sending tiny
branches into the calcified cartilage …

35. The Structure of Subchondral Bone
!
• This is extremely important for cartilage repair: the
tidemark is crossed by collagen fibrils extending
from the articular cartilage into the calcified
cartilage, while no collagen fibrils connect the
calcified cartilage to the subchondral bone plate.
• Blood vessels from the subchondral region can extend into
the overlying calcified cartilage through canals in the
subchondral bone plate.
• Therefore, nutrients can reach chondrocytes in the
calcified zone via these perforations.
• Unsurprisingly, the perforations are grouped
together in the regions of subchondral plate where
the stress is greatest.
CKC UK

36. The Structure of Subchondral Bone
The changes in the thickness of the subchondral bone plate depend on the
location and mechanical loads
Henning Madry, Saarland University, Homburg/Saar, Germany

37. “Vladimir, give me a brief summary …”
From: Vladimir Bobic
Sent: 27 March 2011 10:33
To: Fares Haddad
Subject: Re: cartilage
!
Hi Fares,
!
There is not much new on the horizon. There are quite a few scaffolds/implants, etc, but nothing really exciting. We ("the cartilage people")
seem to be too focused on repairing only one layer (articular cartilage), while we have much bigger structural (and metabolic) problems with an
osteochondral unit. Better understanding of subchondral activity and more 3D approach to repairing the whole (osteochondral) unit rather than just
damaged articulating surface is what we need if we really want to make this work functionally.
As you know from my previous email, there is still a huge unmet need in treating symptomatic chondral and osteochondral lesions as many
articular cartilage procedures fail functionally even with non-impact high-level pro sports. In that respect, and looking honestly at our functional outcomes
of ACI/MACI surgery the best we can do is just to plug the hole (literally) with so-called "functional repair tissue", at enormous expense (over £16,000 for
Genzyme ACI/MACI and over £26,000 for TiGenix CCI!) and reduce athletic population to tears and despair with months of slow and restrictive
rehabilitation. We are definitely not very successful with ACI technology when it comes to anticipated functional outcomes at almost any athletic levels,
although we don't know if this technology helps biologically in the long run.
I don't think that TruFit works in the long run, although the concept is good, but the biological response to biphasic materials is not.
OATS is generally good in the long run, but mainly for smaller lesions and with single 10mm grafts. The surrounding cartilage often fails
(years later) and things get worse circumferentially, often associated with increased subchondral activity (bone marrow oedema) and subchondral cysts
(failed subchondral remodelling), which is probably a consequence of very slow but much wider osteochondral problem at the outset.
I often use deep subchondral decompression through the recipient socket and implant autologous bone marrow aspirate, all of
which seems to work better that OATS on its own. I saw an excellent vet paper in the JBJSA last year, looking at the same combo in horses,
and they confirm that OATS + ABM is better than OATS alone.
I hope this is of some help.
!
Regards, Vladimir
London Knee Meeting 2011
London, 13 October 2011.
Articular Cartilage Repair
one step forward, two steps back … (in 7 minutes)

38. Lateral Femoral Trochlea:
a reliable source of good cancellous bone and bone marrow, even in advanced OA
CKC UK
MFC AVN

39. Autologous Osteochondral Grafting (OATS)

40. Autologous Bone Marrow Aspirate

41. Autologous Bone Marrow Aspirate
AANA Annual Meeting San Francisco 2011

42. Red Bone Marrow
• Red marrow has significant haematopoietic stem cell
potential and still persists in adults in certain areas such as
the iliac crests.
• The anterolateral trochlea (the usual OATS donor site) is
often spared even in advanced OA and seems to contain
reasonably good bone marrow, which can be aspirated
through the donor site.
• Pluripotent haematopoietic stem cells can differentiate into any and
all of the cells of circulating blood and the immune system.
• MRI studies have indicated that the conversion of red to fatty marrow
occurs prematurely in some patients with avascular necrosis.
• Osteonecrosis is associated with a decrease in progenitor cells in the
proximal femur. Bone marrow also contains osteogenic progenitors,
with a potential for effective bone regeneration.
• It seems sensible to use core decompression but also to
deliver better “biologic fuel” with pluripotent cells to the
affected area.
CKC UK

44. JBJS B June 2006

46. An alternative approach to the treatment of
femoral and tibial Osteonecrosis, Chronic SONK
and Secondary OA:
!
• The knee is often not too bad (all 3 compartments) or it is too early
for a partial or a full knee replacement.
• Classic Microfracture and Core Decompression are probably not deep
enough.
• Looking at most MRIs it seems that we need to reach at least 15 to 20
mm deep into subchondral bone, which is where any cylindrical
osteochondral harvesters are very handy.
• Effectively, this is a combination of OAT and deep core (subchondral)
decompression, with a hand driven K-wire, through the bottom of the
recipient socket, with
• a mixture of autologous blood + bone marrow injected into the
recipient socket,
• and capped with 10 mm OATS plug, which was soaked in the same
mixture of bone marrow and blood.
• This “integrated” subchondral repair concept makes sense, it gives
most people quick and durable pain relief and better knee function,
but it is based on huge assumptions.
• The main question is weather unprocessed (and not concentrated)
autologous bone marrow, is powerful enough biologically?
CKC UK

47. • Conclusions: Delivery of bone
marrow concentrate can result
in healing of acute full-thickness
cartilage defects that is superior
to that after microfracture
alone in an equine model.
• If this is the case, looking at
osteochondral defects, is this
combination working better
because microfracture (multiple
perforations and tunnelling) of
subchondral bone is making it less
stiff but also allows “biologic
fuel” (bone marrow, blood and
who knows what else) to reach
deeper areas, re-establish
nutrition and facilitate local
osteochondral repair?
ABMA: An Essential Ingredient for Octeochondral Repair?
JBJS A August 2010

48. MR Right knee (07.01.10): sagittal and
coronal PD/IWFS/T1W volSPGR FS and
axial IWFS sequences.
1. Comparison is made with the previous scan
of 15.09.07.
2. Satisfactory appearances of the ACL
reconstruction as previously.
3. In the medial compartment, an OATS graft
has been placed over the posterior aspect
of the weight-bearing portion of the
MFC, is well integrated with underlying
bone and flush with the articular surface.
There has been reduction in the
subarticular marrow oedema over the
posterior aspect of the MTC but otherwise
the severe degenerative changes and large
intra-articular ossicle lying posteriorly are
unchanged. Subtotal medial
meniscectomy with small, thin, degenerate
middle third remnant.
4. Some repair fibrocartilage and mild
subarticular marrow oedema over the
outer aspect of the upper lateral trochlea
at the donor site.
FU MRI One Year Postop

49. Dear Mr Bobic,
!
I am writing to you to give an update of my progress and to say thanks. You carried out a Medial Subchondral
Decompression, Autologous Bone Marrow Transplant and Autologous Osteochondral Grafting for me on the
7th of January 2009. I found the standard of care you supplied to be excellent. I have had numerous surgeries
over the past twenty years following very poor care provided to me when I was eighteen years old. Yours was the
last procedure I had. Following this my pain has been greatly reduced and my function significantly improved.
To compliment your work, I have worked with a biomechanist to balance and strengthen my body with particular
focus on my legs.
!
Last September, I completed the Yorkshire Three Peaks Challenge which, in case you are not aware, involves
walking a twenty five mile circuit and climbing the highest peaks in Yorkshire. This has to be completed in less
than twelve hours which basically means only two ten to fifteen minute stops. My knee was strong and pain
free for the whole event and the next day provided me with only a small amount of low level aching. There
were plenty of others with no surgical history who were worse off.
!
I would like to thank you very much for making this possible for me. I undertake regular walks in the Lake
District, Yorkshire Dales and Wales and this would not of been even considered before your help.
!
I do understand that I will need a knee replacement in the future and I will not hesitate in coming to see you
for this procedure. Of the many surgeons I have seen I feel the standard of care and expertise you provided was,
by far, the best which has been born out by the excellent result I have had.
!
Thanks again and see you in the future
!
Yours sincerely
From: R... L... <...@btinternet.com>!
Subject: UPDATE AND THANKS!
Date: 12 April 2013 16:08:18 BST!
To: Vladimir Bobic <vbobic@kneeclinic.info>

50. The Future is Cellular!
Thank You