Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Musculoskeletal Disorders
Published in: BMC Musculoskeletal Disorders 1/2020

01-12-2020 | Knee Osteoarthritis | Study protocol

Human adipose-derived Mesenchymal stem cells, low-intensity pulsed ultrasound, or their combination for the treatment of knee osteoarthritis: study protocol for a first-in-man randomized controlled trial

Authors: Mohammad Nasb, Huang Liangjiang, Chenzi Gong, Chen Hong

Published in: BMC Musculoskeletal Disorders | Issue 1/2020

Login to get access

Abstract

Background

Human adipose-derived Mesenchymal stem cells (HADMSCs) have proven their efficacy in treating osteoarthritis (OA), in earlier preclinical and clinical studies. As the tissue repairers are under the control of mechanical and biochemical signals, improving regeneration outcomes using such signals has of late been the focus of attention. Among mechanical stimuli, low-intensity pulsed ultrasound (LIPUS) has recently shown promise both in vitro and in vivo. This study will investigate the potential of LIPUS in enhancing the regeneration process of an osteoarthritic knee joint.

Methods

This study involves a prospective, randomized, placebo-controlled, and single-blind trial based on the SPIRIT guidelines, and aims to recruit 96 patients initially diagnosed with knee osteoarthritis, following American College of Rheumatology criteria. Patients will be randomized in a 1:1:1 ratio to receive Intraarticular HADMSCs injection with LIPUS, Intraarticular HADMSCs injection with shame LIPUS, or Normal saline with LIPUS. The primary outcome is Western Ontario and McMaster Universities Index of OA (WOMAC) score, while the secondary outcomes will be other knee structural changes, and lower limb muscle strength such as the knee cartilage thickness measured by MRI. Blinded assessments will be performed at baseline (1 month prior to treatment), 1 month, 3 months, and 6 months following the interventions.

Discussion

This trial will be the first clinical study to comprehensively investigate the safety and efficacy of LIPUS on stem cell therapy in OA patients. The results may provide evidence of the effectiveness of LIPUS in improving stem cell therapy and deliver valuable information for the design of subsequent trials.

Trial registration

This study had been prospectively registered with the Chinese Clinical Trials Registry. registration number: ChiCTR1900025907 at September 14, 2019.
Literature
1.
Brooks PM. Impact of osteoarthritis on individuals and society: how much disability? Social consequences and health economic implications. Curr Opin Rheumatol. 2002;14:573–7.PubMedCrossRef
2.
Fransen M, Bridgett L, March L, Hoy D, Penserga E, Brooks P. The epidemiology of osteoarthritis in Asia. Int J Rheum Dis. 2011;14:113–21.PubMedCrossRef
3.
Gupta S, Hawker GA, Laporte A, Croxford R, Coyte PC. The economic burden of disabling hip and knee osteoarthritis (OA) from the perspective of individuals living with this condition. Rheumatology. 2005;44:1531–7.PubMedCrossRef
4.
Bijlsma JWJ, Berenbaum F, Lafeber FPJG. Osteoarthritis: an update with relevance for clinical practice. Lancet. 2011;377:2115–26.PubMedCrossRef
5.
Tao J, Liu J, Tu Y, Hu K, Lin M, Guanli X, et al. Different types of exercise relieve pain symptoms of knee osteoarthritis by modulating the cognitive control network. Ann Phys Rehabil Med. 2018;61:e127.CrossRef
6.
Siparsky P, Ryzewicz M, Peterson B, Bartz R. Arthroscopic treatment of osteoarthritis of the knee: are there any evidence-based indications? Clin Orthop Relat Res. 2007;455:107–12.PubMedCrossRef
7.
Röhner E, Windisch C, Nuetzmann K, Rau M, Arnhold M, Matziolis G. Unsatisfactory outcome of arthrodesis performed after septic failure of revision total knee arthroplasty. J Bone Joint Surg Am. 2015;97:298.PubMedPubMedCentralCrossRef
8.
Pak J, Lee JH, Kartolo WA et al. Cartilage regeneration in human with adipose tissue-derived stem cells: Current status in clinical implications. Biomed Res Int. 2016;2016:4702674.CrossRef
9.
Xia P, Wang X, Lin Q, Li X. Efficacy of mesenchymal stem cells injection for the management of knee osteoarthritis: a systematic review and meta-analysis. Int Orthop. 2015;39:2363–72.PubMedCrossRef
10.
Abd-Elsayed A. Stem cells for the treatment of knee osteoarthritis: a comprehensive review. Pain Physician. 2018;21:229–41.PubMedCrossRef
11.
Sekiya I, Muneta T, Horie M, Koga H. Arthroscopic transplantation of synovial stem cells improves clinical outcomes in knees with cartilage defects. Clin Orthop Relat Res. 2015;473:2316–26.PubMedPubMedCentralCrossRef
12.
Horie M, Driscoll MD, Sampson HW, Sekiya I, Caroom CT, Prockop DJ, et al. Implantation of allogenic synovial stem cells promotes meniscal regeneration in a rabbit meniscal defect model. J Bone Jt Surg - Ser A. 2012;94:701–12.CrossRef
13.
Sofia V, Bachri MS, Endrinaldi E. The influence of Mesenchymal stem cell Wharton jelly toward prostaglandin E2 gene expression on Synoviocyte cell osteoarthritis. Open access Maced J Med Sci. 2019;7:1252.PubMedPubMedCentralCrossRef
14.
Leijs MJC, van Buul GM, Verhaar JAN, Hoogduijn MJ, Bos PK, van Osch GJVM. Pre-treatment of human mesenchymal stem cells with inflammatory factors or hypoxia does not influence migration to osteoarthritic cartilage and synovium. Am J Sports Med. 2017;45:1151–61.PubMedCrossRef
15.
Yeatts AB, Choquette DT, Fisher JP. Bioreactors to influence stem cell fate: augmentation of mesenchymal stem cell signaling pathways via dynamic culture systems. Biochim Biophys Acta (BBA)-General Subj. 2013;1830:2470–80.CrossRef
16.
Li D, Zhou J, Chowdhury F, Cheng J, Wang N, Wang F. Role of mechanical factors in fate decisions of stem cells. Regen Med. 2011;6:229–40.PubMedCrossRef
17.
Ongaro A, Pellati A, Bagheri L, Fortini C, Setti S, De Mattei M. Pulsed electromagnetic fields stimulate osteogenic differentiation in human bone marrow and adipose tissue derived mesenchymal stem cells. Bioelectromagnetics. 2014;35:426–36.PubMedCrossRef
18.
Luo F, Hou T, Zhang Z, Xie Z, Wu X, Xu J. Effects of pulsed electromagnetic field frequencies on the osteogenic differentiation of human mesenchymal stem cells. Orthopedics. 2012;35:e526–31.PubMedCrossRef
19.
Ceccarelli G, Bloise N, Mantelli M, Gastaldi G, Fassina L, Cusella De Angelis MG, et al. A comparative analysis of the in vitro effects of pulsed electromagnetic field treatment on osteogenic differentiation of two different mesenchymal cell lineages. Biores Open Access. 2013;2:283–94.PubMedPubMedCentralCrossRef
20.
Uddin SMZ, Qin Y-X. Enhancement of osteogenic differentiation and proliferation in human mesenchymal stem cells by a modified low intensity ultrasound stimulation under simulated microgravity. PLoS One. 2013;8:e73914.PubMedPubMedCentralCrossRef
21.
Koeke PU, Parizotto NA, Carrinho PM, Salate ACB. Comparative study of the efficacy of the topical application of hydrocortisone, therapeutic ultrasound and phonophoresis on the tissue repair process in rat tendons. Ultrasound Med Biol. 2005;31:345–50.PubMedCrossRef
22.
Mitragotri S. Healing sound: the use of ultrasound in drug delivery and other therapeutic applications. Nat Rev Drug Discov. 2005;4:255.PubMedCrossRef
23.
Heybeli N, Yeşildağ A, Oyar O, Gülsoy UK, Tekinsoy MA, Mumcu EF. Diagnostic ultrasound treatment increases the bone fracture–healing rate in an internally fixed rat femoral osteotomy model. J Ultrasound Med. 2002;21:1357–63.PubMedCrossRef
24.
Ikeda K, Takayama T, Suzuki N, Shimada K, Otsuka K, Ito K. Effects of low-intensity pulsed ultrasound on the differentiation of C2C12 cells. Life Sci. 2006;79:1936–43.PubMedCrossRef
25.
Schumann D, Kujat R, Zellner J, Angele MK, Nerlich M, Mayr E, , et al.. Treatment of human mesenchymal stem cells with pulsed low intensity ultrasound enhances the chondrogenic phenotype in vitro. Biorheology. 2006;43:431–443.PubMed
26.
Cook SD, Salkeld SL, Patron LP, Doughty ES, Jones DG. The effect of low-intensity pulsed ultrasound on autologous osteochondral plugs in a canine model. Am J Sports Med. 2008;36:1733–41.PubMedCrossRef
27.
Angle SR, Sena K, Sumner DR, Virdi AS. Osteogenic differentiation of rat bone marrow stromal cells by various intensities of low-intensity pulsed ultrasound. Ultrasonics. 2011;51(3):281–8.PubMedCrossRef
28.
Cui JH, Park SR, Park K, Choi BH, Min B. Preconditioning of mesenchymal stem cells with low-intensity ultrasound for cartilage formation in vivo. Tissue Eng. 2007;13:351–60.PubMedCrossRef
29.
Jiang T, Xu T, Gu F, Chen A, Xiao Z, Zhang D. Osteogenic effect of low intensity pulsed ultrasound on rat adipose-derived stem cells in vitro. J Huazhong U Sci-Med. 2012;32(1):75–81.CrossRef
30.
Jang KW, Ding L, Seol D, Lim TH, Buckwalter JA, Martin JA. Low-intensity pulsed ultrasound promotes chondrogenic progenitor cell migration via focal adhesion kinase pathway. Ultrasound Med Biol. 2014;40(6):1177–86.PubMedPubMedCentralCrossRef
31.
Zhou X, Castro NJ, Zhu W, Cui H, Aliabouzar M, Sarkar K, et al. Improved human bone marrow mesenchymal stem cell osteogenesis in 3D bioprinted tissue scaffolds with low intensity pulsed ultrasound stimulation. Sci Rep. 2016;6:32876.PubMedPubMedCentralCrossRef
32.
Yamaguchi S, Aoyama T, Ito A, Nagai M, Iijima H, Tajino J, et al. Effect of low-intensity pulsed ultrasound after mesenchymal stromal cell injection to treat osteochondral defects: an in vivo study. Ultrasound Med Biol. 2016;42:2903–13.PubMedCrossRef
33.
Chan A-W, Tetzlaff JM, Altman DG, Laupacis A, Gøtzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158:200–7.PubMedPubMedCentralCrossRef
34.
Cao M, Pan Q, Dong H, Yuan X, Li Y, Sun Z, et al. Adipose-derived mesenchymal stem cells improve glucose homeostasis in high-fat diet-induced obese mice. Stem Cell Res Ther. 2015;6:208.PubMedPubMedCentralCrossRef
35.
Alvarez-Viejo M, Menendez-Menendez Y, Blanco-Gelaz MA, Ferrero-Gutierrez A, Fernandez-Rodriguez MA, Gala J, et al. Quantifying mesenchymal stem cells in the mononuclear cell fraction of bone marrow samples obtained for cell therapy. Transplant Proc. 2013;45:434–9.PubMedCrossRef
36.
Peng L, Jia Z, Yin X, Zhang X, Liu Y, Chen P, et al. Comparative analysis of mesenchymal stem cells from bone marrow, cartilage, and adipose tissue. Stem Cells Dev. 2008;17:761–74.PubMedCrossRef
37.
Messingham MJ, Arpey CJ. Update on the use of antibiotics in cutaneous surgery. Dermatologic Surg. 2005;31:1068–78.CrossRef
38.
Zuk PA, Zhu MIN, Mizuno H, Huang J, Futrell JW, Katz AJ, et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 2001;7:211–28.PubMedCrossRef
39.
Goh BC, Thirumala S, Kilroy G, Devireddy RV, Gimble JM. Cryopreservation characteristics of adipose-derived stem cells: maintenance of differentiation potential and viability. J Tissue Eng Regen Med. 2007;1:322–4.PubMedCrossRef
40.
Martinello T, Bronzini I, Maccatrozzo L, Mollo A, Sampaolesi M, Mascarello F, et al. Canine adipose-derived-mesenchymal stem cells do not lose stem features after a long-term cryopreservation. Res Vet Sci. 2011;91:18–24.PubMedCrossRef
41.
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini FC, Krause DS, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8:315–7.PubMedCrossRef
42.
Bennell K, Wee E, Coburn S, Green S, Harris A, Staples M, et al. Efficacy of standardised manual therapy and home exercise programme for chronic rotator cuff disease: randomised placebo controlled trial. Bmj. 2010;340:c2756.PubMedPubMedCentralCrossRef
43.
Celik D, Atalar AC, Sahinkaya S, Demirhan M. The value of intermittent ultrasound treatment in subacromial impingement syndrome. Acta Orthop Traumatol Turc. 2009;43:243–7.PubMedCrossRef
44.
Villafañe JH, Silva GB, Bishop MD, Fernandez-Carnero J. Radial nerve mobilization decreases pain sensitivity and improves motor performance in patients with thumb carpometacarpal osteoarthritis: a randomized controlled trial. Arch Phys Med Rehabil. 2012;93:396–403.PubMedCrossRef
45.
Villafañe JH, Silva GB, Chiarotto A. Effects of passive upper extremity joint mobilization on pain sensitivity and function in participants with secondary carpometacarpal osteoarthritis: a case series. J Manip Physiol Ther. 2012;35:735–42.CrossRef
46.
Stucki G, Meier D, Stucki S, Michel BA, Tyndall AG, Dick W, et al. Evaluation of a German version of WOMAC (Western Ontario and McMaster universities) arthrosis index. Z Rheumatol. 1996;55:40–9.PubMed
47.
Wang Y, Wluka AE, Cicuttini FM. The determinants of change in tibial plateau bone area in osteoarthritic knees: a cohort study. Arthritis Res Ther. 2005;7:R687.PubMedPubMedCentralCrossRef
48.
Lee W, Kim HJ, Kim K, Kim GB, Jin W. Intra-articular injection of autologous adipose tissue-derived Mesenchymal stem cells for the treatment of knee osteoarthritis: a phase IIb, randomized, placebo-controlled clinical trial. Stem Cells Transl Med. 2019;8:504–11.PubMedPubMedCentralCrossRef
Metadata
Title
Human adipose-derived Mesenchymal stem cells, low-intensity pulsed ultrasound, or their combination for the treatment of knee osteoarthritis: study protocol for a first-in-man randomized controlled trial
Authors
Mohammad Nasb
Huang Liangjiang
Chenzi Gong
Chen Hong
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Musculoskeletal Disorders / Issue 1/2020
Electronic ISSN: 1471-2474
DOI
https://doi.org/10.1186/s12891-020-3056-4

Other articles of this Issue 1/2020

BMC Musculoskeletal Disorders 1/2020 Go to the issue

Research article

Comparison between minimally invasive deltoid-split and extended deltoid-split approach for proximal humeral fractures: a case-control study

Research article

Open fenestration discectomy versus microscopic fenestration discectomy for lumbar disc herniation: a randomized controlled trial

Research article

SNHG14 induces osteogenic differentiation of human stromal (mesenchymal) stem cells in vitro by downregulating miR-2861

Research article

Co-existing patterns of MRI lesions were differentially associated with knee pain at rest and on joint loading: a within-person knee-matched case-controls study

Research article

Enhanced recovery care versus traditional non-ERAS care following osteotomies in developmental dysplasia of the hip in children: a retrospective case-cohort study

Research article

Outcomes and potential mechanism of a protocol to optimize foot orthoses in patients with rheumatoid arthritis