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FNU Romaniyanto,1– 3 Ferdiansyah Mahyudin,4,5 Cita Rosita Sigit Prakoeswa,5,6 Hari Basuki Notobroto,7 Damayanti Tinduh,5,8 Ryan Ausrin,2,3 Fedik Abdul Rantam,9,10 Heri Suroto,4,5 Dwikora Novembri Utomo,4,5 Sholahuddin Rhatomy11 1Doctoral Program, Faculty of Medicine, Airlangga University, Surabaya, Indonesia; 2Department of Orthopedic and Traumatology, Prof. Dr. R. Soerharso Orthopedic Hospital, Surakarta, Indonesia; 3Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia; 4Department of Orthopedic and Traumatology, Dr. Soetomo General Hospital, Surabaya, Indonesia; 5Faculty of Medicine, Airlangga University, Surabaya, Indonesia; 6Department of Dermatology and Venereology, Dr. Soetomo General Hospital, Surabaya, Indonesia; 7Faculty of Public Health, Airlangga University, Surabaya, Indonesia; 8Department of Physical Medicine and Medical Rehabilitation, Dr. Soetomo General Hospital, Surabaya, Indonesia; 9Virology and Immunology Laboratory, Microbiology Department, Faculty of Veterinary Medicine, Airlangga University, Surabaya, Indonesia; 10Stem Cell Research and Development Center, Airlangga University, Surabaya, Indonesia; 11Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, IndonesiaCorrespondence: Sholahuddin Rhatomy, Department of Orthopaedics and Traumatology, Dr. Soeradji Tirtonegoro General Hospital, Klaten, Indonesia, Tel +62 272-321163, Fax +62 272-321104, Email doktergustomrhatomy@yahoo.com; sholahuddin.rhatomy@mail.ugm.ac.idAbstract: The intervertebral disc (IVD) is an important structure in the human body because it functions as a weight-bearing. This structure undergoes a process of degeneration like the rest of the body and this process is known as intervertebral disc degeneration (IDD) which is the most common cause of low back pain (LBP). The current common management, either conservative or surgical, is pain-relieving and has not been able to restore degenerated disc optimally. Changes in the IVD microenvironment in IDD conditions make it difficult for the regeneration process to occur. Research to reverse the degeneration process continues to develop, one of them is the use of adipose-derived stem cells (ASCs). ASCs is superior due to the ability to differentiate into several other cells such as adipocytes, chondrocytes, and osteoblasts, it also has ability to act as immunomodulators by stimulating the migration of immune cells to damaged tissues. ASCs becomes a good choice because it is easy to obtain, low donor site morbidity, high proliferation rate, and excellent differentiation abilities. Research on the optimal preparation process for ASCs and their application to various disorders continues to advanced. This study aims to review the potential use of ASCs for regeneration of intervertebral disc degeneration.Keywords: adipose-derived stem cells, stem cell, intervertebral disc, intervertebral disc degeneration, low back pain

Tito Sumarwoto,1,2 Heri Suroto,3 Ferdiansyah Mahyudin,3 Dwikora Novembri Utomo,3 FNU Romaniyanto,2 Andhi Prijosedjati,2 Hari Basuki Notobroto,4 Damayanti Tinduh,5 Cita Rosita Sigit Prakoeswa,6 Fedik Abdul Rantam,7,8 Sholahuddin Rhatomy9,10 1Doctoral Program, Faculty of Medicine, Airlangga University, Surabaya, Indonesia; 2Department of Orthopaedics and Traumatology, Prof Soeharso Orthopaedic Hospital/Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia; 3Department of Orthopaedics and Traumatology, Dr. Soetomo General Hospital/Faculty of Medicine, Airlangga University, Surabaya, Indonesia; 4Faculty of Public Health, Airlangga University, Surabaya, Indonesia; 5Physical Medicine and Rehabilitation Department, Universitas Airlangga, Surabaya, Indonesia; 6Department of Dermatology and Venereology, Dr. Soetomo General Hospital/Faculty of Medicine, Airlangga University, Surabaya, Indonesia; 7Virology and Immunology Laboratory, Microbiology Department, Faculty of Veterinary Medicine, Airlangga University, Surabaya, Indonesia; 8Stem Cell Research and Development Center, Airlangga University, Surabaya, Indonesia; 9Department of Orthopaedics and Traumatology, Dr. Soeradji Tirtonegoro General Hospital, Klaten, Indonesia; 10Faculty of medicine, public health and nursing, Universitas Gadjah Mada, Yogyakarta, IndonesiaCorrespondence: Sholahuddin Rhatomy, Department of Orthopaedics and Traumatology, Dr. Soeradji Tirtonegoro General Hospital, Klaten, Indonesia, Email doktergustomrhatomy@yahoo.comBackground: Brachial plexus injury is an advanced and devastating neurological injury, for which both nerve surgery and tendon transfers sometimes remain insufficient in restoring normal movement. Stem cell therapy may be applicable to rescue the injured motor neurons from degeneration which potentially improves muscle strength.Study Design: Systematic Review; Level of evidence V.Data Sources: A systematic literature search was conducted on PubMed (MEDLINE), EMBASE, the Cochrane Library, and Scopus using the terms (“stem cell”) AND (“brachial plexus”) as search keywords.Methods: The process of study selection was summarized by PRISMA flow diagram. The study included in vivo and in vitro studies with English language, humans or animals with some brachial plexus injuries, interventions, some applications of stem cells to the groups of study, with functional, biomechanical, or safety outcomes.Results: In total, there were 199 studies identified from the literature sources where 75 articles were qualified for forward evaluation following selecting the titles and abstracts. Ten studies were finally included in this systematic review after full-text assessment. Stem cells can produce neurotrophic factors in vitro and in vivo in rats, and their level was increased after injury. Electrophysiological measurement showed that the intervention group had distinctly higher CMAP amplitude and evidently shorter CMAP latency than the model group. Application of bone marrow stem cells (BMSCs) showed an elevation in the numbers of axons and density of myelinated fibers, the density of nerve fibers, the diameter of regenerating axons, and a decrease in axonal degeneration. A study in humans indicated an improvement of the movements in a patient with traumatic total BPI after injection of Ad-MSC. It is associated with increased muscle mass and sensory recovery and also suggested that mononuclear cell injection enhances muscle regeneration and reinnervation in the partly denervated muscle of brachial plexus injury. Various muscle groups had obtained strength together with restoration, the muscle strength attained after the previous transplantation were preserved. The results of this review support stem cell treatment in brachial plexus injury.Conclusion: This review provides evidence of the positive effects of stem cell treatment in brachial plexus injury.Keywords: stem cell, brachial plexus injury, promising therapy

Romaniyanto,1– 3 Ferdiansyah Mahyudin,4,5 Cita Rosita Sigit Prakoeswa,5,6 Hari Basuki Notobroto,7 Damayanti Tinduh,5,8 Ryan Ausrin,2,3 Fedik Abdul Rantam,9,10 Heri Suroto,4,5 Dwikora Novembri Utomo,4,5 Sholahuddin Rhatomy11,12 1Doctoral Program, Faculty of Medicine, Airlangga University, Surabaya, Indonesia; 2Department of Orthopedic and Traumatology, Prof. Dr. R. Soeharso Orthopedic Hospital, Surakarta, Indonesia; 3Faculty of Medicine, Sebelas Maret University, Surakarta, Indonesia; 4Department of Orthopedic and Traumatology, Dr. Soetomo General Hospital, Surabaya, Indonesia; 5Faculty of Medicine, Airlangga University, Surabaya, Indonesia; 6Department of Dermatology and Venereology, Dr. Soetomo General Hospital, Surabaya, Indonesia; 7Faculty of Public Health, Airlangga University, Surabaya, Indonesia; 8Department of Physical Medicine and Medical Rehabilitation, Dr. Soetomo General Hospital, Surabaya, Indonesia; 9Virology and Immunology Laboratory, Microbiology Department, Faculty of Veterinary Medicine, Airlangga University, Surabaya, Indonesia; 10Stem Cell Research and Development Center, Airlangga University, Surabaya, Indonesia; 11Department of Orthopaedics and Traumatology, Dr. Soeradji Tirtonegoro General Hospital, Klaten, Indonesia; 12Faculty of Medicine, Public Health, and Nursing, Universitas Gadjah Mada, Yogyakarta, IndonesiaCorrespondence: Sholahuddin Rhatomy, Department of Orthopaedics and Traumatology, Dr. Soeradji Tirtonegoro General Hospital, Klaten, Indonesia, Email sholahuddin.rhatomy@ugm.ac.idBackground: This study aimed to investigate the effects of hypoxia and normoxia preconditioning in rabbit intervertebral disc-derived stem cells (IVDSCs) and discus-derived conditioned medium (DD-CM)/secretomes in vitro. Transforming growth factor (TGF)-β 1, platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), and vascular endothelial growth factor (VEGF) have a role in the proliferation, development, differentiation, and migration of MSCs.Materials and Methods: Intervertebral discs were isolated from rabbit and incubated in normoxia and hypoxia 1%, 3%, and 5% (hypoxia groups) condition. Cell counting was performed after 24 hours of manipulation, then analyzed using one-way ANOVA. TGF-β 1, PDGF, FGF, and VEGF were measured using the ELISA.Results: The highest number of cells was in the hypoxia 3% preconditioning compared to the normoxia, hypoxia 1%, and hypoxia 5% groups. Hypoxia 3% also had the highest increase in PDGF protein production compared to normoxia, with hypoxia 1% and 5%. Among hypoxia groups, the highest secretions of VEGF and FGF proteins were in the hypoxia 3% group. Based on TGF-β 1 protein measurement, the hypoxia 1% group was the highest increase in this protein compared to other groups.Conclusion: Oxygen level in hypoxia preconditioning has a role in the preparation of IVDSCs and secretome preparation in vitro. The highest cell numbers were found in the treatment group with 3% hypoxia, and 3% hypoxia was significantly related to support IVDSCs preparation. Preconditioning with 3% hypoxia had higher PDGF and VEGF levels than other hypoxia groups.Keywords: intervertebral disc-derived stem cells, secretomes, growth factors, hypoxia, normoxia