## 1 Introduction  
Osteoarthritis (OA) is a multifactorial joint disease that can lead to pain, dysfunction and a decreased quality of life [1]. It is the most common joint disorder, affecting millions of people worldwide [2, 3]; knee OA is one of the main reasons for physical disability [4]. Unfortunately, there is no disease-modifying medical intervention to prevent or cure this disease. Therefore, the mainstay of treatment is focused on symptom relief. Manypatients revert to total joint arthroplasty for definitive management of their OA; however, this is not always a viable option, depending on patient age, surgical risk and medical comorbidities [5]. A widely used conservative treatment measure is intra-articular injection of corticosteroids [2]. Over the past two decades, the use of naturally derived preparations, called orthobiologics, for various orthopedic conditions has become increasingly popular, including for the management of knee OA. This includes the improvement or regeneration of different musculoskeletal tissues by means of biomaterials (e.g., hyaluronic acid (HA)), stem cells and growth factors (e.g., platelet-rich plasma (PRP)) [6; 7]. However, neither intra-articular corticosteroids nor HA and PRP injectables have been recommended for the management of knee OA in the guidelines published by the American Academy of Orthopaedic Surgeons (AAOS) [5; 8]. Cell products were not considered in these guidelines. Basic science studies have found that orthobiologics--unlike corticosteroids--have the potential to improve the condition of the joint rather than just the symptom by modulating inflammation and facilitating cartilage healing [9; 10; 11; 12; 13; 14]. Some of the most frequently used types of orthobiologics include hyaluronic acid (HA) as an important component of the intercellular matrix [15; 16; 17], platelet rich plasma (PRP) [11; 12; 14; 18; 19] and autologous conditioned serum (ACS) [20; 21], as well as cell preparations from stem cell rich sources [22]. Cell products include cultivated mesenchymal stem cells (MSCs) [23], adipose derived mesenchymal stem cells (AD MSC) [24], adipose derived stromal vascular fraction (AD-SVF) [25] and bone marrow aspirate concentrate (BMAC) [26]. Different cell treatments show a significant improvement in functional outcome and in tissue regeneration, resulting in improved radiological outcome parameters [22; 27; 28]. Moreover, MSCs offer the potential for cartilage regeneration owing to their effective immunomodulatory properties and anti-inflammatory abilities [29]. There is growing evidence that PRP has anti-inflammatory characteristics [30], whereas ACS has even superior immunomodulating capacity [20; 21]. PRP treatment has been shown to decrease pain, but no significant disease-altering properties have been consistently reported [5]. PRP augmentation has also been shown as beneficial to accelerate and prolong the therapeutic effect of microfracturation for the treatment of OA [31]. Hylutronic acid injections are thought to work by two separate mechanisms of action [15]. First, the viscoscupmentation lubricates damaged cartilage surfaces, allowing for less friction and inflammation and therefore less joint pain and swelling. Secondly, HA acts as a nutrient for chondrocytes that may still be able to heal when given a more favorable, nutrient-rich environment [15]. Clinical trials have demonstrated its effectiveness for the management of knee OA and superiority to corticosteroid injections when the duration of symptom relief is of concern 16; 17]. The aim of this study was to evaluate the clinical effectiveness of three intra-articular injections (HA, ACS and BMAC) in the treatment of symptomatic knee OA. There are a few studies comparing various kinds of orthobiologics [21; 32; 33; 34]. However, to our knowledge, currently there are no studies simultaneously comparing the outcomes of HA, ACS and BMAC intra-articular injection treatments for the management of knee OA.