This document discusses osteoarthritis (OA) and mesenchymal stem cell (MSC) therapy for OA. It provides an overview of OA, including pathogenesis, risk factors, and current treatment approaches. It then discusses MSCs and their potential therapeutic application for OA, including how MSCs may suppress immune response and inflammation in OA joints. The document notes some safety issues with MSC therapy but also clinical studies showing benefits of MSC treatment for pain relief and functional improvement in OA patients. It describes methods of obtaining MSCs from bone marrow and adipose tissue and regulatory guidelines for preparing cell products in Taiwan.

1. 自體幹細胞治療
退化性關節炎
高雄醫學大學 骨科教授
骨科學研究中心主任
大同醫院骨科主任
陳崇桓

2. Disease of the joints
characterized by:
– Progressive articular
cartilage loss
– New subchondral bone
formation
– New bone and
cartilage formation at
joint margins
– Low level synovitis
Definition of OA
& PAIN!

3. X-rays
• Joint space
narrowing
• Subchondral
sclerosis
• Subchondral cyst
• Spur formation
• Alignment change
(Valgus→varus)

4. 7
7
◼ Non-vascular tissue
◼ Extracellular Matrix :20％
Collagen : Type II collagen
Proteoglycans :Glycosaminoglycan
◼ Water: 70~80％
◼ Chondrocytes: 3 ％
◼ Low numbers of undifferentiated cells.
◼ Limited regenerative capability (Buckwalter et
al,1998)
Articular Cartilage
http://www.noc.nhs.uk/hipandknee/information/knee/conditions/arthritis.
aspx
7
(Heinegård, D. et al. Nature Review Rheumatol 2011)

5. Core Protein
Glycosaminoglycans
Link
Protein
Hyaluronic
Acid
Proteoglycan
monomer
Proteoglycan
aggregate
Proteoglycan Aggregate
Glycosaminoglycans
e.g. Chondroitin sulfate, Keratan
sulfate (polysaccraride chains
containing GLUCOSAMINE)

6. Pathogenesis in OA
• Decreases in:
– GAG synthesis
– Size of Aggregates,
GAG & Hyaluronic acid
– Collagen x-linking
– Water content
• Chondrocyte apoptosis
• Traumatic damage

7. Osteoarthritis (OA)
Higher incidence of OA in elderly
⚫2020: 595 million people had OA, 7.6% of the
global population
⚫2050: increase 74.9% for knee, 48.6% for hand,
78.6% for hip, and 95.1% for other types of OA
Lancet Rheumatol 2023; 5: e508–22

8. High incidence of OA in Taiwan
Lancet Rheumatol 2023; 5: e508–22

9. Knee OA most

11. OA in Taiwan
• > 65 y/o: 11.53%
• >70 y/o: 70% have knee OA
• Knee OA total medical cost: 3.06 billion
NT
• Patients with clinic visit due to knee OA:
528,000
http://www.moi.gov.tw/stat/news_content.aspx?sn=8057
http://www.doh.gov.tw/CHT2006/DM/DM_2.aspx? NOW fod
list_no=12029&class_no=440&level_no=3
http://www.doh.gov.tw/CHT2006/DM/DM_2.aspx? NOW fod
list_no=12025&class_no=440&level_no=3

12. Risk Factors for OA
Systemic Risk Factors
• Age
– 10-fold increase from 30→65
• Genetics (generalized)
• Gender
– Men <50: lower risk
– Women >50: higher risk
• Nutritional
– Low vitamin C and D intake
Joint Biomechanical Risk
Factors
• Joint trauma
• Obesity (knee, hip, hand)
• Occupation
• Abnormal joint
biomechanics
– Dysplasia, malalignment,
instability, abnormal
innervation
• Knee extensor wkness
• Sports w/ joint risk

13. Post-traumatic OA (PT-OA)
• Ligamentous or capsular Injury in joint:
increase >10-fold of OA risk
• Articular fracture:
increase > 20-fold of OA risk
• In USA: 6 million PT-OA p’ts
3 billion USD for treating PT-OA
Anderson et al, JOR 2011

14. • Nonpharmocologic Measures
– Education, Weight loss, Exercise, &
Bracing
• Pharmacologic Measures
– Analgesics, Glucosamine, Injectables
• Alternative Therapies
– Acupuncture, Magnets, Balneotherapy,
Thermotherapy
• Surgery
Treatment of Osteoarthritis
Overview

15. • OA is a complex syndrome rather than a
single disease.
• OA subgroups can be characterized based
on differences in prognosis, therapeutic
response or disease mechanisms.
• OA phenotyping includes the identification
of key phenotypic characteristics,
appropriate statistical approaches and
extensive validation.

18. • OA is a painful chronic disease, and the
associated pain mechanisms are complex.
• Peripheral sensitization and central
sensitization contribute to OA pain.
• Nociceptive, inflammatory and
neuropathic pains are part of the OA pain
phenotype but are differentiated by
mechanisms.

20. • Inflammatory pathways, cartilage and
subchondral bone are the three main targets for
the development of disease-modifying OA drugs.
• Some existing therapeutic agents, such as
bisphosphonates, strontium and hyaluronic acid,
may act as potential disease-modifying OA drugs.
• Non-pharmacological treatments are likely to
provide alternatives for disease modification in
OA.

22. Mesenchymal stem cell

24. • Anti-nerve growth factor therapy is a promising
therapeutic for OA pain, despite reported
adverse effects.
• Therapies for OA pain are rapidly transforming
beyond traditional painkillers toward more
mechanism-based interventions.
• Neurolysis is being investigated for OA pain,
but efficacy profiles and long-term effects
require further study

25. Neurotrophin, NGF
• Expression is markedly increased in human
pain states, including OA
• Profound sensitizing effects on the nociception
• Tanezumab (Pfizer and Eli Lilly), fasinumab
(Regeneron and Teva) and fulranumab
(Janssen and Amgen)
• Anti-NGF therapy: rapidly progressive OA and,
less commonly, with osteonecrosis,
• FDA hold on all clinical trials of NGF
antagonists in 2010. Restart 2015

26. 2019 OARSI guideline

35. 2019 ACR

38. 46
JAMA. 2021;325(6):568-578.

39. Pathophysiology: synovitis
• The synovitis seen in OA has a predominance of
macrophages, while the synovitis of RA has a
predominance of T cells. This reflects activation of the
innate immune response in OA joints, likely due to
damage of joint tissues resulting in a chronic wound type
of environment.
• OA synovitis is more focal than in RA; in the knee, it is
commonly found in the suprapatellar pouch.
• Synovitis plays a prominent role in joint destruction in RA,
while its role in the progression of OA may be limited to a
subset of individuals.

42. Treatment

46. Stem Cell therapy

47. Unique characteristics of Stem
Cells
• Stem cells can regenerate
– Unlimited self renewal through cell division
• Stem cells can specialize
– Under certain physiologic or experimental
conditions
– Stem cells then become cells with special
functions such as:
• Beating cells of the heart muscle
• Insulin-producing cells of the pancreas

48. Potential of Stem Cells
• Totipotent (total):
– Total potential to differentiate into any adult cell
type
– Total potential to form specialized tissue needed
for embryonic development
• Pluripotent (plural):
– Potential to form most or all 210 differentiated adult
cell types
• Multipotent (multiple):
– Limited potential
– Forms only multiple adult cell types
• Oligodendrocytes
• Neurons

49. http://www.stemcellresearch.org/testimony/20040929prentice.htm Reprinted with permission of Do No Harm.

50. Stem cells application
• Stem cells are undifferentiated cells that
have many potential scientific uses:
– Cell based therapies
• Often referred to as regenerative or reparative
medicine
– Therapeutic cloning
– Gene therapy
– Cancer research
– Basic research

51. Stem cells
• Embryonic stem cell (hESC) (pluripotent or
totipotent)
• Induced pluripotent stem cells (iPSCs)
(pluripotent)
• Mesenchymal stem cells (MSCs) (multipotent)
• In 2016, 351 US businesses engaged in
frequently unproven and direct-to-consumer
marketing of different stem cell interventions was
offered at 570 clinics

52. Embryonic stem cells

53. Ethical issues
(Embryo Destruction)

54. Induced pluripotent stem cells
(iPSCs)

55. Safety issues regarding iPSC-
based therapy
Undifferentiated iPSCs are not safe
• As for hESCs the main safety issue regarding iPSC-
based therapy is the risk of teratoma formation which
can happened if patient receive iPSC-derived cells that
contain undifferentiated Ipsc
• Uncontrolled proliferation and differentiation of
transplanted undifferentiated iPSCs may result in
generation of tumors and/or undesired differentiation of
iPSCs in broad range of somatic cells

56. Mesenchymal stem cells
(MSCs)

57. Safety issues regarding MSCs-
based therapy
• Despite these promising results, safety issues
regarding MSCs-based therapy are still a matter
of debate, especially in the long-term follow up
• The primary concern is unwanted differentiation
of the transplanted MSCs and their potential to
suppress anti-tumor immune response and
generate new blood vessels that may promote
tumor growth and metastasis.

58. MSC之再生醫學應用
6
9
Stem. Cell. Res. Ther. 2021; 16: 323-353.
Many clinical trials based on MSCs for the treatment of
a variety of diseases, demonstrating their capability in
the treatment of dermatological, musculoskeletal,
neurological, cardiovascular, respiratory, renal,
gastroenterological and urological conditions, etc.

59. MSC 治療骨關節炎 MSC-based suppression
of immune response in
osteoarthritis
- Suppress migration of macrophages and reduce their capacity to
produce
pro-inflammatory TNF-α
- Inhibit maturation of DCs and alter their secretion profile resulting in
decreased production of TNF-α
- Directly decrease production of Th1 and Th17 cytokines in effector T
cells
- Decrease activation and proliferation of autoreactive B lymphocytes
Pharmacother. 2019 ; 109: 2318-2326.

60. Schematic representation of the potential therapeutic
strategies utilizing mesenchymal cells (MSCs)
therapy for cartilage repair and regeneration.
Biomedicines. 2021; 9: 785.

61. Int. J. Mol. Sci. 2023, 24, 9939

62. Difficulties of Stem Cell Therapy
• Autologous without expansion: limited cell
number (>10 million cells)
• Stem cell products: (autologous or allogeneic)
GTP, CMC, high cost
• IPSCs: GTP, CMC, high cost,
risk of transformation

63. Int. J. Mol. Sci. 2023, 24, 9939

64. Bone-marrow-MSC

65. Bone-marrow aspiration
concentrate (BMAC)

66. Adipose derived-MSC

67. Adipose derived-MSC

68. Other MSC

70. • Autologous adipose-derived stem cells (ASCs) and
adipose-derived stromal vascular fraction (ADSVF)
• 7 RCT
• Superior pain relief (P < 0.0001 ; P < 0.00001)
• Significantly improved function (P < 0.009; P = 0.005).
• Significant improvement in cartilage (P < 0.000001; P <
0.00001).

73. • 28 studies, 3594 patients, 70% knee
• Adipose-derived stem/stromal cells
(ADSCs): 26%, stromal vascular fraction
(SVF): 72%;
• Significantly higher score in ADSCs than
SVF (p = 0.0027).
• High heterogeneity
J. Clin. Med. 2023, 12, 4719

74. 85
特管法及細胞產
品製造實驗室規
格

75. 86
2018年衛生福利部發布「特定醫療技術檢查檢驗醫療儀器施行或使用管理辦法」
台灣

76. ❖醫療機構：高雄市立大同醫院(委託財團法人私立高雄醫學大
學經營)
❖操作醫師：傅尹志、陳崇桓、王應鈞
• 細胞治療項目 自體脂肪幹細胞移植
• 適應症 退化性關節炎及膝關節軟骨缺損
• 目的
利用自體脂肪幹細胞治療退化性關節炎及膝骨關節軟
骨缺損，修復受損之膝骨關節，緩解病患之臨床不適
症狀
• 醫療機構類別 100床以上醫院
目前特管法申請之計畫(通過)

77. 88
* 依據2005年美國FDA發佈實施法案內容:
-實驗室硬體要有極高規格
-必須為正壓實驗室
-無塵室潔淨等級必須達一萬級
-P3等級生物安全操作臺，
獨立空調進排氣口，完全分離的人流、
物流動線，恒溫恒濕
GTP規範實驗
製備細胞產品的實驗室:
- 為Good Tissue Practice (GTP)
規範實驗
- 通過2023年台美能力試驗
細胞製備場所所屬機構:

78. 分析項目 規格
黴漿菌 不得檢出
無菌試驗-好氧菌 不得檢出
無菌試驗-厭氧菌 不得檢出
內毒素含量 <0.25 EU/ml
傳染病源 檢測名稱
HBV HBs Ag
HBV Anti-HBc Ab
HCV Anti-HCV Ab
HTLV I&II Anti-HTLV-I, II
HIV I&II HIV Ab1+2 Combo
梅毒 RPR
(1) 病原菌篩檢合格 (3) 高純度幹細胞
分析項目 規格
CD11b ≤ 2 %
CD19 ≤ 2 %
CD34 ≤ 2 %
CD45 ≤ 2 %
HLA-DR ≤ 2 %
CD73 ≥ 95%
CD90 ≥ 95%
CD105 ≥ 95%
(2) 高品質幹細胞
幹細胞嚴格品管
(4) 24小時電腦警示監控系統
不斷電系統，確保細胞儲存之品質

79. 施行計畫摘要-
治療事件時間表
(1個月) (3個月) (6個月) (12個月)

80. 療效評估方式
醫師專業評估
• 疼痛視覺類比量表(Visual Analog Scale for pain, VAS pain)
• 西安大略及麥可麥司特大學關節炎量表 (Western Ontario and
McMaster Universities Osteoarthritis Index, WOMAC)
• 膝關節炎疼痛指數評分表(Lequesne's index)
• IKDC（International Knee Documentation Committee）
• KOOS（Knee injury and Osteoarthritis Outcome Score）
• Tegner Lysholm Knee Scoring Scale
• 治療前後X-ray的影像評估
病人觀感&病人生活品質
生活品質量表 (The MOS 36-item short-form health survey,
SF36)
療效會依總分數做評估:
-有療效:
總分數比治療前之總分數高於(含)10%
-沒有療效:
總分數比治療前之總分數低於10%

81. Take home message
• OA treatment: according to
– Stage
– Patient condition
– Life quality demanding
• No medication for cure, only palliative
– Treatment goal and side effect
• Surgery for end stage OA if condition
suitable
• Stem cell therapy maybe helpful

82. Thanks for your attention