關節內注射間葉幹細胞於治療動物創傷性及退化性關節病之實證醫學研究與犬隻臨床應用之效用評估

Evidence-based study of intra-articular mesenchymal stem cell injection in animals with traumatic and degenerative arthropathies and evaluation of clinical therapeutic effects in dogs

蔡聲揚(Shen-Yang Tsai)

指導教授 ： 葉力森

國立臺灣大學/獸醫專業學院/臨床動物醫學研究所/碩士(2011年)

https://doi.org/10.6342/NTU.2011.02536

摘要

骨關節炎(osteoarthritis, OA)，又稱退化性關節病(degenerative joint disease, DJD)是一種非炎症性退化性的關節軟骨病變，無論人或動物，此疾病皆為中老年族群中最常見的問題之一。軟骨本身很差的再生能力再加上目前仍無有效逆轉病程的治療方式，也造成了骨關節炎在處理上的複雜性。

由於幹細胞具有分化的能力，能夠藉由新生組織，達到適當修復及癒合的效果，近年來已受到再生醫學領域的高度關注。以關節注射方式植入幹細胞，屬微創的外科治療方式，就機制上來說，間葉幹細胞有能力促進軟骨的新生及抑制關節內的發炎反應，進而延緩甚至改善關節炎的病程，故有機會成為關節炎治療的替代療法之一。

本研究第一部分，將利用系統性文獻搜尋的方法，以實證醫學的角度，探討動物關節內注射間葉幹細胞於治療骨關節病之臨床成效。研究共納入11篇動物相關研究文獻，種別包含鼠、兔、豬、羊、馬及犬隻，文中詳列出文獻所提之受試動物、研究材料、評估方式、試驗結果…等，並以美國FDA網站公布之實證醫學指導原則，針對各文獻實驗設計及研究方法的品質做分級。結果顯示，因相關研究極少，且各研究間之實驗異質性大，無法進行統合分析提出一有效之結論，不過就個別研究成果來看，以關節內注射提供間葉幹細胞的治療方式，大多數結果顯示的確能在關節內進行某種程度的組織修復效果。

第二部分的研究，將利用豬隻脂肪來源的異種間葉幹細胞，治療犬隻骨關節炎，並評估其治療效果。受試動物包含三隻臨床上患有膝部退化性骨關節炎的犬隻，以關節注射方式，植入每個關節約500萬個間葉幹細胞。關節炎病程評估方式包括：主觀性之骨科學檢查評量、飼主問卷評量，以及客觀性之放射學檢查與犬隻步態測力板分析。結果顯示在經過間葉幹細胞關節注射治療的三隻犬隻，無論是骨科學檢查、飼主問卷及測力板數據皆顯示能減緩膝部骨關節炎之症狀，進而達到患肢功能上的改善。

雖然以關節內注射間葉幹細胞之治療方式於實驗動物及臨床上的初步成果皆顯示有某種程度的治療效果，然而間葉幹細胞關節內作用機制尚未完全被證實，因此在將此療法納入常規治療前，其治療劑量、合適療程、介入時間點…等相關資訊，仍需經過日後更多大規模臨床試驗的證實。

關鍵字

間葉幹細胞 ； 成體幹細胞 ； 關節注射 ； 骨關節炎 ； 退化性關節病 ； 實證醫學

並列摘要

Osteoarthritis, also referred as degenerative joint disease(DJD), is a disease process associated with non-inflammatory, degenerative changes in the tissues of synovial joints and loss of articular cartilage, it is a common diagnosis in the clinic of aged population in both human and veterinary medicine. The poor regenerative capacity of cartilage and no available curative treatment options complicate satisfactory management of osteoarthritis.

Recently, stem cell therapy plays an important role in regenerative medicine due to its capacity to differentiate into new tissue to achieve proper tissue repair. Intra-articular injection of suspended stem cells, as a minimal invasive surgical option, could provide as an alternative therapy to osteoarthritis due to its effect of cartilage regeneration and immunomodulation mechanism, and therefore, stop or reverse the disease progression of osteoarthritis.

In chapter three, we systematically review the articles related to intra-articular mesenchymal stem cell injection in animals and consider them in the light of evidence-based (veterinary) medicine. A total of 11 studies from various animal species including rat、rabbit、porcine、goat、horse and dog were included. The study materials, evaluation methods and primary outcome of each study were analysed along with the evaluation of the study design and grading of the study quality by use of the FDA’s EBM scoring system. Evaluation of efficacy in published trials was hampered by the low number of studies and their heterogeneity nature, but most of individual study shows intra-articular stem cell injection could have positive therapeutic effect to a certain degree.

In chapter four, we use porcine adipose-derived mesenchymal stem cells as a stem cell source to treat canine osteoarthritis and evaluate its therapeutic effects. A total of 3 client-owned dogs with nature course of stifle degenerative joint disease were included in our study. We delivered approximately 5x106 stem cells per joint suspended in phosphate buffered saline via direct intra-articular injection. The outcome revealed that the score of doctor assessment, owner assessment, peak vertical force and vertical impulse of affect limb were functionally improved after intra-articular injection of mesenchymal stem cells.

Although some studies, whether in experimental animal models or in clinical trial, have provided promising results of intra-articular stem cell therapy in osteoarthritis, the information is still limited. The actual mechanism of stem cells participating in tissue repair, optimal number of cells needed to be injected, proper therapeutic protocols or the appropriate time point of intervention still remains to be discovered in the future.

並列關鍵字

mesenchymal stem cell ； adult stem cell ； intraarticular injection ； osteoarthritis ； degenerative joint disease ； evidence-based medicine

參考文獻

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