An overview of orthopaedic stem cell applications presented at the 3rd meeting of the Biological Knee Society, Cardiff, UK, on 3rd February 2017

1. Autologous Stem Cell Therapies
in Knee Orthopaedics
New developments which may delay or avoid more invasive surgical treatments?
The future of orthopaedics? Less carpentry, more biology?
Prof. Vladimir Bobić
Chester Knee Clinic www.kneeclinic.info office@kneeclinic.info @ChesterKnee
The 3rd Meeting of the Biological Knee Society
Cardiff 3 February 2017

2. Less (orthopaedic) carpentry - more biology?

6. 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

8. Cell Senescence Exists but ...

9. Regenerative Medicine - Stem Cell Technologies

10. Recent Webinars

11. Biotechnologies - Stem Cell Technologies

12. Stem Cells No Better Than Placebo … So Far
(Editor of Arthroscopy Journal re JBJSA September 2016 Article)

17. 1st Orthopaedic
Stem Cell Seminar in
the UK:
Guest Speaker:
Dr Fabio Valerio Sciarretta
Head of Department of Orthopeadic Surgery at
Mercede Clinic, Rome, Italy.
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.
www.fabiosciarretta.it

20. 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
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MEDICINE CENTRE
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21. From Chondral Damage to Advanced OA
... to Advanced Medial OA?From Small MFC Chondral Lesion ...

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

23. OsteoArthritis or OsteoArthrosis?
or just wear and tear?

24. 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

25. 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 …

26. 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

27. 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

28. Arthroscopy Journal, article in press, 2015

29. Arthroscopy Journal, article in press, 2015

30. PRP Today

31. PRP

32. OJSM 2017

33. “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)

34. • Mainly because we still do not seem to understand
complex biological and mechanical interaction of
articulating surface and subchondral bone.
• This is probably the reason why all mainstream
cartilage repair technologies suffer from two major
problems:
• insufficient peripheral chondral integration
(biomechanical problem?)
• insufficient longitudinal subchondral integration
(nutritional and biomechanical problem?).
• We may have to accept that this is as good as it
gets, at this point in time.
• However, 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.
So, Why is Cartilage Repair Still a Problem?

36. 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.

39. Saw et al.:Arthroscopy 2013

41. Chondrogenesis: Contained Lesion

42. Chondrogenesis: Uncontained Lesion

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

46. 13th ICRS World Congress, Sorrento September 2016

47. SVF Adipose Tissue MSCs

48. •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?

54. 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.”

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

56. Autologous Bone Marrow Aspirate

57. JBJSA March 1974

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

59. Autologous 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.
• The quantity and quality of good autologous bone marrow is
questionable, but as it seems that stem cells do not to do the
actual work (they seem to go around and boss other cells and
tell them where to go and what to do) a few mils of bone
marrow aspirate may be good enough to kick-start the process.
CKC UK

61. JBJS B June 2006

62. SONK Before and After Subchondral Decompression
• 15/12/08: subarticular insufficiency
fracture and slight flattening of the
MFC and prominent subarticular
marrow oedema more marked on the
femoral side. Since 04/04/08,
significant deterioration in the medial
compartment with SONK-like
process, progressive degenerative
changes …
• 11/09/09: Comparison is made with
the previous scan 15/12/2008. In the
medial compartment, following the
subchondral decompression, there
is now evidence of articular
irregularity, deficiency and
thinning of articular cartilage,
slight increase in the subarticular
marrow oedema and early
subarticular cyst formation in the
outer aspect of the MFC …

63. SONK: sudden onset,
severe knee pain
MRI: “In the outer weight-
bearing portion of the medial
femoral condyle, there is an
osteochondral lesion (22mm ant-
post x 10mm med-lat x 2mm
deep), with fluid at the interface
with parent bone, mild reactive
marrow oedema and a cortical
break peripherally in keeping
with instability. Degenerative
changes in the medial
compartment with spontaneous
osteonecrosis of the medial
femoral condyle (SONK) and
unstable fragment.”
David Ritchie, Glasgow
CKC MRI 060506

64. FU MRI: “In the medial
compartment, the graft over the
central weight-bearing portion of
the medial femoral condyle has
incorporated with adjacent
bone and the overlying
articular cartilage is flush
with adjacent native
cartilage. A small focus of
marrow oedema is noted directly
beneath the graft but overall
there has been a reduction in
marrow oedema around the
graft. A small trace of
subcortical fluid in the peripheral
portion of the medial femoral
condyle is similar to the pre-
operative scan - presumably not
included in the repair.”
Dr David Ritchie, Glasgow
CKC MRI 030307

65. The Subchondroplasty Procedure

68. 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

69. • 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

70. 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>

71. This applies both to stem cell
technologies and our attitudes …
"There are only two ways to live your life:
One is as though nothing is a miracle.
The other is as though everything is a miracle."
Albert Einstein

72. The Future is Cellular!