Autologous Mesenchymal Stem Cells in Orthopaedics

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

From Chondral Damage to Advanced OA:

... to Advanced Medial OA?From Small MFC Chondral Lesion ...

Osteochondral Repair and OA: Current Treatment Options

ACI BioPoly

TKR

OATS

Microfracture

Chondroplasty

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

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.

|

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

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.

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

The Telegraph, Sunday 14 April 2013

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

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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: [email protected]

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Saw et al.: Arthroscopy 2013

Chondrogenesis: Contained Lesion

Chondrogenesis: Uncontained Lesion

Saw et al.: Arthroscopy 2011

Gradual Regeneration of Articular Surface

•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?

SVF Adipose Tissue MSCs

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.”

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.

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.

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.

Autologous Osteochondral Grafting

and Bone Marrow Aspirate

Vladimir Bobic Chester Knee Clinic

JBJSA March 1974

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 …

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

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

“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 2011London, 13 October 2011.

Articular Cartilage Repair one step forward, two steps back … (in 7 minutes)

Lateral Femoral Trochlea: a reliable source of good cancellous bone and bone marrow, even in advanced OA

CKC UK

MFC AVN

Autologous Osteochondral Grafting (OATS)

Autologous Bone Marrow Aspirate

Autologous Bone Marrow Aspirate

AANA Annual Meeting San Francisco 2011

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

JBJS B June 2006

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

• 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

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

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... <[email protected]>!Subject: UPDATE AND THANKS!Date: 12 April 2013 16:08:18 BST!To: Vladimir Bobic <[email protected]>

The Future is Cellular!

Thank You