Stem cell therapy for OA knee?

1. Stem cell treatment for
OA knee: Hype or Promise?
LI Kwok Ho/ LING Sau Ying/ NG Ka Man Joanna/ SHUM Miranda Jing Man
TSAI Hung Yu/ TSUI Hon Lung Keith/ WONG Wai Yip

2. Outline
• Part 1 – Osteoarthritis of knee, pathogenesis,
current treatments and limitations
• Part 2 – Mesenchymal stem cells
• Part 3 – Use of MSCs in OA knee treatment,
literature review

3. Part I – OA pathogenesis,
current treatment options
and limitations

4. Part I - Osteoarthritis
• One of most common degenerative
diseases
• One of most common causes of
disability in elderly
• Progressive joint disease with loss
of articular cartilage
• Most commonly in weight-bearing
joints e.g. knee, hip joints
• Symptomatic knee OA affects:
• 12% adults in the U.S.
• 15.0% women and 5.6% men in
Chinese aged 60 or above
(The Beijing Osteoarthritis Study
2001)

5. Pathogenesis
- Dynamic process:
Tissue production v.s.Remodeling of joint
- Major role: Articular cartilage changes
Healthy joint
Cartilage matrix rich in
collagen and proteoglycans
OA
 Proteolytic matrix degradation
 Chondrocytes increases matrix
synthesis, esp. at maximum
load bearing
 New fibrocartilage undergone
ossification  Osteophytes
 Subchondral bone changes 
subchondral sclerosis,
subchondral cyst

7. Current treatment options
Non-pharmacologic
• Exercise program, weight reduction,
land-based or aquatic exercise
Pharmacologic:
• Panadol, NSAIDs, intra-articular
steroids, opioid anaglesics
• Intra-articular hyaluronates
Surgical:
• Joint irrigation, debridement
• Chondrocyte grafting
• Knee arthroplasty
(unicompartmental / total joint
replacement)
JAAOS
July 2010vol. 18 no. 7 406-416

8. … … But limitations
• Only improve pain and function
• None of them are disease modifying
• Articular cartilage cannot be regenerated
• Side effects of medications …
• Chondrocyte grafting looks appealing
• Limited in use of focal cartilage defects due to trauma
• Need donor site
• Hype or promise?
Mesenchymal stem cells (MSC) for OA knee tx

9. Part II -
Mesenchymal stem cells

10. Different Levels of Stem Cell State

13. FGF-2
TFG-β

14. Mode of isolation
• Surface markers allows for identification and isolation:
• CD146, CD105, VCAM1

16. Function
• Regenerative
• Multipotent
• Self-renewal
• Others
• Growth factors
• Organize vascular networks
• Trophic, inflammatory or immune modulatory???

17. Other promises
• Gene therapy in stem cells
• Adenosine deaminase severe combined immunodeficiency
• Epidermolysis bullosa
• Possible genetic skeletal disease to be corrected by
gene therapy targeting stem cells
• Osteogenesis imperfecta
• Fibrous dysplasia

19. Part III:
MSCs in OA knee

20. Treatment of OA
• AAOS recommended
• Pharmacological: NSAID/Tramadol
• Other treatments: Intra-articular hyaluronic acid injection,
physical therapy, glucosamine, acupuncutre, autologous
chondrocyte implantation……
Symptomatic relief? Maintaining joint function?
X Regenerate joint cartilage

21. Why OA cannot be cured?
Poor intrinsic repair
capacity of cartilage

22. Aim of Stem cell therapy in OA
• Maintenance or restoration of a fully functional joint with
biomechanically stable articular cartilage

23. MSCs
• Unlike chondrocytes
• Not limited by availability of healthy articular cartilage
• Not affected by intrinsic tendency of the cells to lose their
phenotype during expansion
• Do not need for a cartilage biopsy
• Avoids damage to the donor-site articular surface

24. Sequence of events
1. Harvest of MSCs
2. Preparation of MSCs
3. Delivery into the osteoarthritic knee
4. Post-operative rehabilitation

25. 1. Harvest of MSCs
• Bone marrow-derived MSC
• More superior capacity for chondrogenesis
• Adipose- derived MSC
• 500x more than that found in bone marrow
• Easily assessable, non-invasive repeatable
harvesting method
• Relatively little donor site morbidity
• Cultured more easily and grow more rapidly
• Proliferation and differentiation potential are
less affected by age
• Better immunosuppressive properties

26. 2. Preparation of MSCs
• Isolation:
• Adherence to cell-culture
plastic
• Density-gradient
fractionation
• Culture medium:
• Fibroblast growth factor 2
(FGF-2)
• Transforming growth factor
β (TGF- β)
• Monolayer expansion for
positive selection for
chondroprogenitor cells

27. 3. Delivery into the osteoarthritic knee
• Cell-loaded 3D solid scaffold
• For focal cartilage defects
• Late OA with bony component:
exposed subchondral bone
• Implanted via open arthrotomy
• More invasive
• Increase risk of joint infection
• Kissing lesion may readily and rapidly
worn down the matrix

29. 3. Delivery into the osteoarthritic knee
• Direct intra-articular injection
• For early OA, pure cartilage damage
• Cartilage lesions in OA knee
• Large
• Unconfined, affect >1 locations
• Opposed/ ‘Kissing’ lesions common

30. How much does it cost?
• US$5000-10,000 per injection

31. Advantages of MSCs in OA repair
• Simple
• Ease of MSC delivery
• Minimum invasiveness
• Avoiding the potential disease transmission caused by
the xenograft coverage used in Autologous Chondrocyte
Implantation (ACI)
Treatment of osteoarthritis with mesenchymal stem cells
Stem cells and regenerative medicine June 2014 Vol.57 No.6: 586–595

32. Literature review
• Intervention: Intraarticular injection of BM-MSCs into OA knee
• Harvested from iliac crest, 24 weeks follow up
2008

33. Literature review
• 18 patients (mean age 54.6 years old)
• Visual analog scale > grade 4 for at least 4 months
• Kellgren-Lawrance grade 3 in multiple compartmemt/ grade 4 in 1
compartment
• Intervention: Intraarticular injection of A-MSCs into OA knee
(doses of 1.0x 106 cells)
• Harvested from inner side of the infrapatellar
fat pad by skin incision
2013

35. Limitation of this study
• Improvement may be contributed by arthroscopic
treatment before injection
• Synovectomy, debridement or excision of tears of menisci/
fragments of articular cartilage, chondral flaps, or
osteophytes
• Infrapatellar fat pad is not a good source for A-MSCs

36. Literature review
• 18 patients (mean age 63 years old)
• Visual analog scale > grade 4 for at least 4 months
• Kellgren-Lawrance grade 3 (12) – 4 (6)
• Intervention: Intraarticular injection of A-MSCs into OA
knee in doses of 1.0x 107/ 5.0x 107/ 1.0x 108 cells
Abdominal subcutaneous fat
2014

37. Results - Clinical improvement
WOMAC
p=0.003
KSS
Knee
score
p<0.001
VAS pain
p<0.001
KSS
Function
Score
p<0.020

38. Results: Radiological improvement

39. Results: Radiological improvement

40. Results: Arthroscopic improvement

41. Results: Histological confirmation
• Biopsy specimen from medial femoral condyles
• Before injection: no cartilage
• 6 months after injection:
• Thick glossy white cartilage with smooth surface
• Well integration with subcondral bone
• Lower ½ of middle zone & Deep zone: Type II collagen hyaline
like cartilage, Safranin O
• Superficial & upper ½ of middle zone: Type I collagen
fibrocartilage

42. Limitation of this study
• No control group
• Short follow up: 6 months only
• Quality of regenerated cartilage not optimal as in
histological results

43. Unsolved mysteries
1. Best cellular dose and injection frequency?
– free bodies of scar tissue in high dose injection,
single or multiple dose
2. Variable function and potency among different
subtypes of MSCs – which one is the best?
3. Unknown in vivo behavior of implanted MSCs in host
tissue: survive/ integrate into newly formed tissue?
4. Induced to chondrogenesis before implanted in vivo? –
improved cartilage regeneration in sheep model

44. Summary

45. Summary
• Osteoarthritis
• Mesenchymal stem cells (Adipose vs
bone marrow)
• Literature results and limitations
• Future development

46. References
1. High revalence of lateral knee osteoarthritis in Beijing Chinese compared with
Framingham Caucasian subjects. Felson DT, Nevitt MC, Zhang Y, et al. Arthritis Rheum
2002;46:1217-22
2. Total knee arthroplasty for primary knee osteoarthritis: changing pattern over the past
10 years. Yan, CH; Chiu, KY; Ng, FY. Hong Kong Med J. 2011 Feb;17(1):20-5.
3. Increased Knee Cartilage Volume in Degenerative Joint Disease using Percutaneously
Implanted, Autologous Mesenchymal Stem Cells Pain Physician 2008; 11:3:343-353
4. Intra-Articular Injection of Mesenchymal Stem Cells for the Treatment of Osteoarthritis
of the Knee: A Proof-of-Concept Clinical Trial CHRIS HYUNCHUL JO,YOUNG GIL
LEE,WON HYOUNG SHIN,HYANG KIM,JEE WON CHAI, Stem cells 2014;32:1254-
1266
5. Mesenchymal Stem Cell Injections Improve Symptoms of Knee Osteoarthritis Yong-Gon
Koh, M.D., Seung-Bae Jo, M.D., Oh-Ryong Kwon, M.D.,
6. The meaning, the sense and the significance: translating the science of mesenchymal
stem cells into medicine. Bianco P, Cao X, Frenette PS, Mao JJ, Robey PG, Simmons
PJ, Wang CY. Nat Med. 2013 Jan;19(1):35-42.

47. Acknowledgement
Special thanks to Dr. Terrance Pun