## 1 Introduction  
Osteoarthritis (OA) is a highly common condition that can affect any joint in the body. Its main features are articular degeneration, cartilage destruction, and inflammation [1]. Due to the increasing life expectancy, its incidence is expected to rise [2]. The prevalence of ankle AO is less than 1% of the adult population [3]. Rarely idiopathic, ankle AO is largely due to trauma [4, 5]. The main risk factors for ankle AO include deformity, whether congenital or acquired, rheumatic disease, malleolar fracture, and ankle sprains sustained during sport activities. As a result, younger patients with high functional demands are affected more frequently [6, 7, 8]. Ankle OA adversely influences quality of life by impairing the activities of daily living. Athletes clearly experience even more severe limitations [9]. Current OA management guidelines differ in relation to patient age, functional demands, and disease severity. Conservative approaches include weight loss, orthotics, physical therapy, analgesics, non-steroidal anti-inflammatory drugs, and intra-articular injections of substances such as hyaluronic acid (viscosupplementation), corticosteroids, and platelet-rich plasma (PRP) [10, 11]. In recent years, the interest in non-pharmacological therapies has been mounting, as a rising number of patients demand \"natural\" treatments. Orthobiologic treatment employs natural, i.e., biological substances to manage patients with orthopedic conditions. These substances are derived from donors or, more often, from the patient's own tissues, and are used to help musculoskeletal lesions-such as bone fractures and muscle, tendon, and ligament lesions-to heal more rapidly [12]. The rationale for their effectiveness is the fact that they are applied at a higher concentration than naturally occurs in the body [13]. These substances include bone grafts, autologous blood, PRP, autologous conditioned serum, and stem cells. Stem cells have the unique ability to reconstitute tissues where the presence of a high amount of dead or dying cells hampers regeneration. There are two main types of stem cells. Embryonal stem cells are found exclusively in the early stages of fetal development, whereas mesenchymal stem cells (MSCs) are found throughout life [14]. Key features of stem cells are their ability to self-renew and differentiate into multiple cell types [15]. Notably, stemness involves the ability to maintain the pool of stem cells and to generate daughter cells capable of differentiating into specialized cells and tissues. MSCs can be isolated from a number of mesenchymal tissues such as bone marrow, synovial membrane, peristoeum, and adipose tissue and can differentiate to cartilage as well as tendon and bone cells [15]. In recent years, a novel orthobiologic substance, micro-fragmented adipose tissue (MAT), has increasingly been used to foster tissue-healing in patients with knee and ankle OA [16; 17]. MAT has been reported to have marked anti-inflammatory and regenerative properties both in vivo and in vitro; it is administered as an intra-articular injection and involves a very low rate of complications [18; 19]. The Lipogens(r) system (Lipogems International S.p.a., Milano, Italy) is a class II medical device that is used to reduce the size of adipose tissue clusters [20]. It produces MAT by mechanical disaggregation of the lipoasprate and by the separation and elimination of blood residues and pro-inflammatory oil. MAT is then rapidly injected into the painful joint. The effects of MAT include vascular stabilization and the inhibition of several macrophage functions that characterize the inflammation process of a wide range of orthopedic and dermatological conditions [21; 22; 23]. Although several studies have reported promising results in patients with OA treated with intra-articular MAT, additional information is required [24]. In particular, data on the outcomes of ankle OA treated with autologous MSCs derived from adipose tissue (ADSCs) are limited, especially where athletes are concerned [17].