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

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

Part I – OA pathogenesis, current treatment options and limitations

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)

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

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

… … 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

Part II - Mesenchymal stem cells

Different Levels of Stem Cell State

FGF-2TFG-β

Mode of isolation

• Surface markers allows for identification and isolation:

• CD146, CD105, VCAM1

Function

• Regenerative

• Multipotent

• Self-renewal

• Others

• Growth factors

• Organize vascular networks

• Trophic, inflammatory or immune modulatory???

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

Part III:MSCs in OA knee

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

Why OA cannot be cured?

Poor intrinsic repair capacity of cartilage

Aim of Stem cell therapy in OA

• Maintenance or restoration of a fully functional joint with biomechanically stable articular cartilage

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

Sequence of events

1. Harvest of MSCs

2. Preparation of MSCs

3. Delivery into the osteoarthritic knee

4. Post-operative rehabilitation

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

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

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

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

How much does it cost?

• US$5000-10,000 per injection

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

Literature review

• Intervention: Intraarticular injection of BM-MSCs into OA knee

• Harvested from iliac crest, 24 weeks follow up

2008

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

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

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

Results - Clinical improvement

WOMACp=0.003

KSS Knee scorep<0.001

VAS painp<0.001

KSS Function Scorep<0.020

Results: Radiological improvement

Results: Radiological improvement

Results: Arthroscopic improvement

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

Limitation of this study

• No control group

• Short follow up: 6 months only

• Quality of regenerated cartilage not optimal as in histological results

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

Summary

Summary

• Osteoarthritis

• Mesenchymal stem cells (Adipose vs bone marrow)

• Literature results and limitations

• Future development

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.

Acknowledgement

Special thanks to Dr. Terrance Pun