The social impact of degenerative diseases such as articular cartilage pathology is steadily increasing, because of the continued rise in the mean age of the active population. Articular cartilage lesions are generally, but not always, associated with disability and with symptoms such as joint pain and reduced function, and might progress to end-stage osteoarthritis (OA). Varieties of non-invasive solutions for pain relief, improvement in function and disability, and eventually, modification of the progression of severe cartilage lesions and OA, have been proposed with variable success rates [
1‐
3]. Non-surgical treatments, such as physiokinesitherapy, pharmacological treatments (analgesics/anti-inflammatory agents, glucocorticoids, opioids, nonsteroidal anti-inflammatory drugs - NSAIDs), hyaluronic acid (HA) or its derivatives [
4,
5] or platelet-rich plasma (PRP) injections [
6,
7], indicated for small or diffused degenerative lesions, temporarily target the symptoms but cannot prevent the degeneration process [
8]. Joint-preserving surgical treatments, such as arthroscopic shaving or debridement, laser chondroplasty, and microfractures, provide temporary relief of symptoms, but the clinical findings are highly variable and many authors contraindicated their use for diffused joint degeneration. For these reasons, new therapeutic approaches, such as the use of mesenchymal stem cells (MSCs) have been developed. Through trophic, mitogenic, anti-scarring, anti-apoptotic, immunomodulatory, and anti-microbial actions, produced by a large amount of bioactive elements, growth factors and cytokines, MSCs “sense” and “signal” changes in the microenvironment where they reside [
9,
10]. Bone marrow and adipose tissue are the most readily available sources of MSCs, and, in this context, the adipose tissue is nowadays considered the smartest due to its abundance, the easy access and the simple isolation procedure [
11,
12]. In addition, of the many cell types contained in the adipose tissue, MSCs (ASCs) comprise up to 2%, whereas only 0.02% of cells in bone marrow are MSCs. The use of ASCs, either culture-expanded or obtained by mechanical or enzymatic treatment as stromal vascular fraction (SVF) [
13] have recently created a huge interest in the context of cartilage regeneration and shown promising results [
14‐
18]. However, the studies published to date used a tissue-engineering approach, involving the use of scaffolds, cells, and growth factors, either alone or in any combination [
16,
19‐
21]. In addition to the large number of processing steps, the high economic burden, and the restrictions associated with cell expansion and extensive manipulation [
22,
23], the results achieved to date are far from being completely satisfactory. Therefore, availability of a minimally manipulated adipose tissue providing in one-step the key elements to support a natural regenerative response would have remarkable clinical relevance [
24]. Based on these considerations, a commercially available technique that intra-operatively provides micro-fragmented and minimally manipulated adipose tissue without expansion or enzymatic treatment [
25] was employed in this study. This approach, that has been already shown to be safe and promising in different pathologies [
26‐
33], provides the key elements to support a natural reparative response, that is scaffold (the adipose tissue structure), cells (ASCs), and growth factors (secreted cytokines and chemokines) [
34]. The aim of this retrospective study is to explore whether patients affected by symptomatic knee OA treated with micro-fragmented adipose tissue injection associated with a chondral shaving procedure experience an improvement in symptoms and function.