Autologous micro-fragmented adipose tissue injection provides significant and prolonged clinical improvement in patients with knee osteoarthritis: a case-series study
Journal of Experimental Orthopaedics volume 10, Article number: 116 (2023)
Among the conservative strategies to manage patients with symptomatic knee osteoarthritis (OA), an innovative approach exploiting the regenerative capability of adipose tissue and its resident MSCs (Mesenchymal Stem Cells or Medicinal Signalling Cells) has been proposed with encouraging results. This study aims to demonstrate the benefits of autologous micro-fragmented adipose tissue (MAT) injection in the conservative treatment of knee osteoarthritis and whether any variables may affect the outcome. This is a case series single-centre study in which patients underwent intraarticular MAT injection without any associated procedures.
Based on inclusion and exclusion criteria, 49 patients (67 Knees) were included and retrospectively analysed with a mean follow-up of 34.04 ± 13.62 months (minimum 11 – maximum 59). Patients were assessed through the WOMAC and KOOS questionnaires at baseline (pre-treatment) and 1-, 3-, 6-, 12-, 24- and 36-month follow-up. A minimal clinically important difference (MCID) of at least 7.5 points for the WOMAC pain scale and 7.2 for the WOMAC function scale compared to the baseline value was used.
WOMAC and KOOS scores improved after treatment compared to baseline at all follow-ups with p < 0.001. Male gender and Kellgren-Lawrence (KL) grade 2 were associated with smaller improvement in WOMAC and KOOS scores (with respect to females and to KL grade 1, respectively) up to 24 months. The percentage of patients who reach the MCID for WOMAC pain is generally lower than that of patients who reach the MCID for WOMAC function (around 80% at all time points), but it increases significantly over time. Moreover, the baseline score of the WOMAC pain and function influence the outcome. Patients with worse symptoms are more likely to reach the MCID.
Intra-articular knee injection of MAT for the treatment of knee osteoarthritis (KOA), recalcitrant to traditional conservative treatments, proved to be effective in a high percentage of cases. The positive association between a worse pre-operative score and a better clinical response to the treatment would support the idea that intra-articular administration of MAT could be considered in patients with very symptomatic KOA in which joint-replacement surgeries are not indicated (or accepted).
Level of Evidence
IV, case series.
Among the conservative strategies to manage patients with symptomatic knee osteoarthritis (KOA), intra-articular injections of corticosteroid or hyaluronic acid (HA) have shown satisfactory results in the last decade [1,2,3,4]. However, these treatments have not allowed for proven efficacy in changing/reverting the natural history of the disease in many patients [3, 5].
Platelet-rich plasma (PRP) has been advocated as an alternative injective treatment option, given the anti-inflammatory effect of blood growth factors [6, 7]. However, the results are controversial, mainly because of the need for more agreement on the specific PRP formulation and application protocol. Recently, an innovative approach exploiting the regenerative capability of adipose tissue and its resident MSCs (Mesenchymal Stem Cells or Medicinal Signalling Cells) has been proposed with encouraging results [8, 9]. Indeed, extensive in vitro and ex vivo research activity focused on the identification and explanation of the mechanisms of action of MSCs has clearly shown the influence of MSC paracrine activity on reducing inflammation and promoting matrix turnover in osteoarthritis (OA) .
Nevertheless, preparing autologous MSCs for injection would require ex vivo culture from a good manufacturing practice facility, which makes the process laborious and expensive [10,11,12]. Therefore, the availability of a minimally manipulated adipose tissue providing regenerative components in one step is of remarkable clinical relevance and equal effectiveness . Among the available techniques, this research employed a commercial system that provides micro-fragmented and minimally manipulated adipose tissue without expansion or enzymatic treatment . Micro-fragmented adipose tissue (MAT) is obtained through a mild mechanical tissue cluster size reduction in a full immersion closed system. It has already been shown to be safe and promising in different pathologies [12, 15,16,17]. In particular, the intra-articular injection of MAT for KOA showed early promising results [18,19,20]. In the literature, several authors have shown how gender, BMI and a higher degree of KOA can influence the clinical response to treatment with MSC [21, 22].
Therefore, the targets of the study are to evaluate If any parameters can influence the response to the treatment with intra-articular injection of MAT for symptomatic KOA; if a good and stable clinical outcome (measured by the Minimal Clinical Important Difference, MCID) is maintained over time and if pre-operative scores of WOMAC and KOOS can influence the MCID.
Study design and patient selection
This is a case series single-centre study conducted over four years. From April 2018 to September 2022, 49 patients (67 knees) underwent autologous MAT intraarticular knee injection in a highly specialised orthopaedic centre (Humanitas Castelli Hospital, Bergamo, Italy). The ethics committee approved the following study (protocol number 35/23 GAV, CET Lombardia 5). Patients’ demographics are presented in Table 1. The inclusion and exclusion criteria are reported in Table 2.
Clinical assessment and data collection
Patients were evaluated at baseline, during the pre-treatment screening, at 1-, 3-, 6-, 12-, 24-, and 36-months follow-up. Baseline demographics data, BMI, and medical history, including previous conservative and surgical treatments of the target knee/s, were collected. Clinical examination was performed on all the patients. Anteroposterior weight-bearing x-rays of both knees, lateral-lateral, and Merchant view x-rays of the target knee/s were ordered during the pre-surgical screening. In our treatment protocol, the indication for autologous and micro-fragmented adipose tissue intraarticular injection in patients with a KL grade 4 was allowed only upon the patient refused a surgical knee replacement option.
Patients completed WOMAC and Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaires at baseline (pre-treatment) and 1-, 3-, 6-, 12-, 24- and 36-months follow-up. The clinical examination was performed by an investigator not involved in the surgical indication or injection treatment. A minimal clinically important difference (MCID) of at least 7.5 points for the WOMAC pain scale and 7.2 for the WOMAC function scale compared to the baseline value was used, according to Holtz et al. . Furthermore the MCID of at least 10 points for the WOMAC total score compared to the baseline value was used, according to Clement et al. .
The adipose tissue harvesting and processing has been previously described . In summary, the lower or the lateral abdomen was chosen as the donor site for adipose tissue harvesting. Before harvesting the fat, the site was injected with an irrigation solution composed of NaCl 0.9% 250 mL, 200 mg/10 ml of mepivacaine 2% (two vials) and 0.5 mg/0.5 mL of adrenaline (1/2 vial). The fat was then harvested using a 13G blunt cannula connected to a Vaclock® 20-ml syringe. The harvested fat was immediately processed in the Lipogems® processing kit (Lipogems International Spa, Milan, Italy). This disposable device progressively reduces the size of the adipose tissue clusters with a mild mechanical action while eliminating oily substances and blood residues with pro-inflammatory properties. The resulting micro-fragmented fat was collected in a 60 ml syringe, positioned for decanting the excess saline solution, and then transferred into several 10 ml syringes to be injected into the patient. Micro-fragmented fat was injected intra-articular in a volume of 10 ml in each knee.
Post-op rehabilitation protocol
All patients wore an elastic compression band on the harvesting site for 2–3 weeks during the postoperative period. In addition, patients were administered painkillers in the immediate post-op upon request and low molecular weight heparin for ten days. The postoperative protocol was five days of unloading, then full load recovery in the following five days, active and passive motion from the immediate post-op, and proprioceptive exercises from day five post-op.
Analyses were performed using R software v4.1.3 (R Core Team, Vienna, Austria) . Continuous data distribution was assessed by the Shapiro–Wilk test. Parametric or non-parametric tests were performed according to the result of this test. One-Way ANOVA test with Tukey’s post hoc test for pairwise comparison (or Kruskall-Wallis with Dunn’s post hoc test for non-normal data) was used to assess differences among time points or more than two different categories. Student t-test or Mann Whitney U test was used for comparisons between two subgroups. Multilevel linear models were selected based on AIC minimization criteria to evaluate the effect of different variables on the change in clinical outcomes and to adjust estimations for patients treated bilaterally. In addition, analyses were repeated, excluding patients treated bilaterally. P values < 0.05 were considered statistically significant.
Functional score improvements after treatment
WOMAC score showed improvements after treatment compared to baseline at all follow-ups with p < 0.001. Further significant improvements were observed comparing the 3-month WOMAC score with 6- (p = 0.016), 12- (p = 0.002), and 24-month (p = 0.019) evaluations. Figure 1 shows the reduction in WOMAC score compared to the baseline for all time points. Absolute values are reported as well as for each grade of KL classification (Tables 3, 4, 5 and 6).
Multilevel linear regression models were used to test the association of different variables to changes in WOMAC score. Male gender was associated with higher WOMAC score (with respect to females) up to 24 months (p = 0.053). KL grade 2 was also associated with higher WOMAC scores with respect to KL grade 1, especially at 24 months when this difference was close to statistical significance (p = 0.088) (Table 7).
Similarly, KOOS showed significant improvements at all follow-ups (p < 0.001 at 6-, 12-, 24- and 36-months) with respect to baseline. No differences were observed among follow-ups (Fig. 4). Absolute values are reported as well as for each grade of KL classification (Tables 8, 9, 10 and 11).
As per WOMAC, changes in KOOS were associated with gender and KL grade. In particular, males showed a lower mean increase compared to females (ranging from -13.3 to 19.4 points, depending on the different follow-ups), even if only at 6 and 12 months, this difference was significant. KL grade 2 was associated with lower improvement up to -26.2 points at 24-month follow-up compared to subjects with KL grade 1 (p = 0.042) (Table 12).
Functional score and Minimal Clinically Important Difference (MCID)
WOMAC pain, function and total score
The percentage of patients who reach the MCID for WOMAC pain is generally lower than that of patients who reach the MCID for WOMAC function, but it increases significantly over time. Otherwise, the percentage of patients reaching the MCID for WOMAC function remains around 80% at all time points. The same was observed for WOMAC total score (Table 13).
Influence of baseline values on MCID in WOMAC pain, function and total score
Baseline WOMAC pain values are significantly different between those who achieve the MCID and those who do not attain it at different times (excluding 36 months) (Table 14).
Similarly, the WOMAC function values at baseline are also significantly different between those who achieve the MCID and those who do not at different times (excluding 36 months) (Table 15). The same was observed for WOMAC total score (Table 16).
KOOS pain, symptoms, ADL, sport, QOL
At 6 and 12 months, the percentages of subjects who reach the MCID in the various subscales are shown in the table (Table 17).
Influence of baseline values and follow-up on MCID in KOOS subscales
For Pain, Symptoms, ADL and Sports subscales (even if only at 6 months), a statistically significant difference between the baseline values of KOOS is noted between those who reach the MCID and those who do not reach it, with worse baseline values for those who reach it (Table 18).
The most common complication in this study was knee swelling and pain, occurring in 7 (10,4%) knees. Moreover, three patients (6%) reported some ecchymosis on their abdomen which was self-limited. There can be considered mild adverse events after this type of procedure. All of these cases were treated with cryotherapy, common analgesics and rest for a few days. No severe adverse event was recorded. At the final follow-up, no patients underwent TKA.
The main finding of this study was that the intra-articular knee injection of micro-fragmented adipose tissue (MAT) allowed for a significant and stable improvement of all the clinical outcomes at 24 months follow-up. Moreover, this study showed that the male gender and a higher degree of KL determine a more contained clinical response. These results align with Gobbi et al., which showed that the male gender and a higher degree of KL are associated with reduced improvement after MAT injection. The same author has shown that ageing can also affect the clinical response. The present study did not show this correlation, but it must be kept in mind that the mean age of the enrolled patients (59.4) is lower than that of Gobbi et al. (70.7) . Data from this study agree with those reported by a recent meta-analysis by Kim et al. that showed significant pain relief at 6 months and 12 months and functional improvement at 6 months and 12 months post-injection . In addition, the stable improvement in KOOS and WOMAC scale in our cohort is similar to those of Roato et al., that showed improvement in WOMAC and VAS after 18 months of follow-up  and to those of Spasovski et al.  and Hudetz et al. , as well. Furthermore, no severe adverse event was recorded, confirming the safety profile already demonstrated [16, 17, 20, 29]. Nevertheless, caution in using this treatment is still recommended, especially since mild adverse events (knee pain, joint swelling, and injection site pain) can occur in the first weeks after treatment. Therefore it is essential to educate the patient .
The use of adipose tissue as a source of regenerative cells has increased over the last few years. This is because adipose tissue offers several advantages over other cell sources, such as bone marrow, including minimal invasive harvesting and a higher yield of regenerative cells. Moreover, mesenchymal stem cells from adipose tissue have been demonstrated to possess higher immunomodulatory and thropic activity than bone marrow cells [31,32,33].
Microfragmentation of adipose tissue is a convenient and safe way to exploit its regenerative capability in a one-step technique. In addition, the MAT used in this study has been characterised by an intact stromal vascular niche rich in mesenchymal cells , and some authors supported the idea that these peculiar features can increase the treatment efficiency compared to other methods [35, 36].
In this study a total of 49 subjects (67 knees) were enrolled with a mean follow-up of 34.04 ± 13.62 months. All scores improve significantly from 3 months after treatment, continue to improve up to 6 months (n = 67), and then remain stable for up to 24 months. During the follow-up, no patient underwent prosthetic surgery.
Regarding the therapeutic effect of MAT injections on the achievement of MCID, Garza et al.  showed that 62% of their treatment group had a WOMAC score above MCID at 6 months. In contrast, Freitag et al.  showed that 94.4% of their treatment group were above MCID at 12 months. However, expanded adipose tissue MSCs were used in this cohort. Recently, Zaffagnini et al. showed how a single MAT injection was not superior to PRP injection; moreover, both MAT and PRP provided significant and similar clinical improvement up to 24 months of follow-up. The radiographic evaluation with the KL classification did not show any worsening in KOA severity at the final follow-up for both treatment groups . Gobbi et al. performed a Randomized Clinical Trial comparing MAT with leukocyte‑poor platelet‑rich plasma plus hyaluronic acid with a 2 years follow-up. They showed that both treatments lead to significant clinical improvement without a relevant difference between each other within a cohort of patients with KL grades 1–2  with an improvement in KOOS score in line with the results of this research.
In the present study, the percentage of patients who reach the MCID for WOMAC pain is generally lower than that of patients who reach the MCID for WOMAC function (around 80% at all time points), but it increases significantly over time. These steady results were also reported by Cattaneo et al. , although their patients received an arthroscopic surgery in addition to MAT injection and are in line with what emerged from a recent meta-analysis that showed a steady with a slight decrease in WOMAC score after 24 months .
Regarding KOOS scores, the results of the present study are in line with those of Boffa et al., which showed that PRP injections for KOA provide stable responsiveness at 6 and 12 months follow-up with encouraging results in terms of MCID (> 80% of patients at each follow-up) . Moreover, the authors highlighted how the female sex is associated with a better clinical response, confirming what emerged from the present study.
The study also highlighted how the MCID is influenced by the baseline score of the WOMAC; in fact, patients with worse symptoms are more likely to improve. This evidence has already been highlighted by Schiavone Panni et al. about the VAS scale . A possible interpretation relies on the fact that a worse baseline score condition might reflect a higher inflammatory status of the joint. In fact, it is known that adipose-derived MSCs are very responsive to inflammation [44,45,46], higher levels of inflammatory mediators might activate more the pro-regenerative activity of MAT, eventually determining a higher clinical outcome. These observations were emphasised by Heidari et al., that showed highly statistically significant improvement in clinical outcome and quality of life at 2 years follow-up in patients with a bad pre-operative OKS score . In addition, some initial findings have demonstrated an efficient response of chondrocytes and proteoglycan synthesis following MAT injection, as observed by Boric et al., which used functional MRI to assess glycosaminoglycan content in hyaline cartilage. At 24 months follow-up, they showed a significant increase in the glycosaminoglycan content, suggesting the positive effects of MAT injections . This might challenge the natural course of ageing and OA processes, including the loss of proteoglycans in the extracellular matrix . If confirmed, this would have enormous implications since other conservative or surgical treatments have never shown precise results that support their capacity to modify the natural history of the disease.
These results allow us to consider adipose tissue-derived MSCs as a possible second-line injective therapeutic alternative for a large population cohort affected by OA, with apparently better results as emerged from the study of Dallo et al., from which it emerges that adipose tissue-derived MSCs showed better clinical results in Tegner and KOOS symptoms at six months and Tegner at 12 months than leucocyte-poor platelet-rich plasma (LP-PRP) plus hyaluronic acid (HA) . Indeed, this study is only based on clinical findings; therefore, the subjective patient perception could have also had a relevant role. However, in a previous study, the authors evaluated objective data such as the N-glycan profile in synovial fluid by UPLC analysis and glycosaminoglycan content in articular cartilage by dGEMRIC (delayed gadolinium-enhanced magnetic resonance imaging of cartilage)-enhanced MRI. While the first analysis failed to find any possible difference between values at baseline and at 12-month follow, the dGEMRIC index showed an improvement in 53% of the patients and a worsening in 15% of them after autologous microfragmented adipose tissue injection. This would suggest a different response of patients to the treatment, although the lack of clinical findings for these patients, except for the VAS score, does not allow for any direct correlation between subjective satisfaction and imaging results .
The present study has several limitations, including the small number of patients and a wide range of follow-ups. Another limitation was the assessment of clinical outcomes only, without any imaging or biochemical evaluation of the possible effect of the treatment on cartilage tissue. The lack of a control group exposes the data of the present study to a possible bias linked to the placebo effect, well highlighted and documented by the recent meta-analysis by Previtali et al. . Moreover, the lack of a control group could overestimate the results of the present study, in which emerged a great clinical response in patients with lower scores. A good clinical response could also be justified by the use of painkillers or as a result of proprioceptive exercises that each patient is advised to undergo after MAT injection.
At the same time, it is of great importance that some patients who reached a follow-up of 40 months maintained an improvement in clinical outcomes without resorting to surgical procedures. The presence of several patients treated bilaterally may be considered a limitation of the study. Indeed, analyses performed excluding these patients suggested a more relevant role for continuous variables (age, in particular), rather than categorical (gender and KL grade), possibly due to the lower number of subjects included in each category. Nevertheless, the statistical approach used in the study, i.e., multilevel modelling, allows accounting for the correlation of data deriving from bilateral patients and provides net estimation of the effects of all variables whilst avoiding excluding patients from the analysis.
A strength of this study is that it complied with almost all the points of the MIBO guidelines checklist  and the absence of surgical procedures, such as arthroscopic procedures associated with adipose tissue-derived MSCs. Compared to previous works by the same author [17, 20], this study highlighted the potential of adipose tissue-derived MSCs without confounding factors that could alter the clinical scores.
Intra-articular knee injection of MAT represents an effective and safe second-line injective treatment for KOA recalcitrant to traditional conservative treatments, with a stable and prolonged effect. Furthermore, it can be considered in patients with moderate to severe knee symptoms based on the positive association between a worse pre-operative score and a better clinical response or in which joint-replacement surgeries are not indicated (or accepted). However, to establish if this treatment may be proposed as an early approach to knee OA, more specific studies, possibly with longer follow-up, are needed to analyse the biological impact of intra-articular injection of MAT on the natural history of the disease.
Bannuru RR, Osani MC, Vaysbrot EE, Arden NK, Bennell K, Bierma-Zeinstra SMA, Kraus VB, Lohmander LS, Abbott JH, Bhandari M, Blanco FJ, Espinosa R, Haugen IK, Lin J, Mandl LA, Moilanen E, Nakamura N, Snyder-Mackler L, Trojian T, Underwood M, McAlindon TE (2019) OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage 27(11):1578–1589
Cole BJ, Karas V, Hussey K, Merkow DB, Pilz K, Fortier LA (2017) Hyaluronic acid versus platelet-rich plasma: a prospective, double-blind randomized controlled trial comparing clinical outcomes and effects on intra-articular biology for the treatment of knee osteoarthritis. Am J Sports Med 45(2):339–346
Deyle GD, Allen CS, Allison SC, Gill NW, Hando BR, Petersen EJ, Dusenberry DI, Rhon DI (2020) Physical therapy versus glucocorticoid injection for osteoarthritis of the knee. N Engl J Med 382(15):1420–1429
Di Martino A, Di Matteo B, Papio T, Tentoni F, Selleri F, Cenacchi A, Kon E, Filardo G (2019) Platelet-rich plasma versus hyaluronic acid injections for the treatment of knee osteoarthritis: results at 5 years of a double-blind, randomized controlled trial. Am J Sports Med 47(2):347–354
Zhao J, Huang H, Liang G, Zeng L, Yang W, Liu J (2020) Effects and safety of the combination of platelet-rich plasma (PRP) and hyaluronic acid (HA) in the treatment of knee osteoarthritis: a systematic review and meta-analysis. BMC Musculoskelet Disord 21(1):224
Dong Y, Zhang B, Yang Q, Zhu J, Sun X (2021) The effects of platelet-rich plasma injection in knee and hip osteoarthritis: a meta-analysis of randomized controlled trials. Clin Rheumatol 40(1):263–277
Shen L, Yuan T, Chen S, Xie X, Zhang C (2017) The temporal effect of platelet-rich plasma on pain and physical function in the treatment of knee osteoarthritis: systematic review and meta-analysis of randomized controlled trials. J Orthop Surg 12(1):16
de Girolamo L, Kon E, Filardo G, Marmotti AG, Soler F, Peretti GM, Vannini F, Madry H, Chubinskaya S (2016) Regenerative approaches for the treatment of early OA. Knee Surg Sports Traumatol Arthrosc 24(6):1826–1835
Ma W, Liu C, Wang S, Xu H, Sun H, Fan X (2020) Efficacy and safety of intra-articular injection of mesenchymal stem cells in the treatment of knee osteoarthritis: a systematic review and meta-analysis. Medicine (Baltimore) 99(49):e23343
Lopa S, Colombini A, Moretti M, de Girolamo L (2019) Injective mesenchymal stem cell-based treatments for knee osteoarthritis: from mechanisms of action to current clinical evidences. Knee Surg Sports Traumatol Arthrosc 27(6):2003–2020
Kim K-I, Kim M-S, Kim J-H (2023) Intra-articular injection of autologous adipose-derived stem cells or stromal vascular fractions: are they effective for patients with knee osteoarthritis? A systematic review with meta-analysis of randomized controlled trials. Am J Sports Med 51(3):837–848
Naldini G, Sturiale A, Fabiani B, Giani I, Menconi C (2018) Micro-fragmented adipose tissue injection for the treatment of complex anal fistula: a pilot study accessing safety and feasibility. Tech Coloproctology 22(2):107–113
Filardo G, Tschon M, Perdisa F, Brogini S, Cavallo C, Desando G, Giavaresi G, Grigolo B, Martini L, Nicoli Aldini N, Roffi A, Fini M, Kon E (2022) Micro-fragmentation is a valid alternative to cell expansion and enzymatic digestion of adipose tissue for the treatment of knee osteoarthritis: a comparative preclinical study. Knee Surg Sports Traumatol Arthrosc 30(3):773–781
Bianchi F, Maioli M, Leonardi E, Olivi E, Pasquinelli G, Valente S, Mendez AJ, Ricordi C, Raffaini M, Tremolada C, Ventura C (2013) A new nonenzymatic method and device to obtain a fat tissue derivative highly enriched in pericyte-like elements by mild mechanical forces from human lipoaspirates. Cell Transplant 22(11):2063–2077
Bisicchia S, Bernardi G, Pagnotta SM, Tudisco C (2020) Micro-fragmented stromal-vascular fraction plus microfractures provides better clinical results than microfractures alone in symptomatic focal chondral lesions of the knee. Knee Surg Sports Traumatol Arthrosc 28(6):1876–1884
Cattaneo G, De Caro A, Napoli F, Chiapale D, Trada P, Camera A (2018) Micro-fragmented adipose tissue injection associated with arthroscopic procedures in patients with symptomatic knee osteoarthritis. BMC Musculoskelet Disord 19(1):176
Russo A, Condello V, Madonna V, Guerriero M, Zorzi C (2017) Autologous and micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis. J Exp Orthop 4(1):33
Hudetz D, Borić I, Rod E, Jeleč Ž, Kunovac B, Polašek O, Vrdoljak T, Plečko M, Skelin A, Polančec D, Zenić L, Primorac D (2019) Early results of intra-articular micro-fragmented lipoaspirate treatment in patients with late stages knee osteoarthritis: a prospective study. Croat Med J 60(3):227–236
Polancec Z, Hudetz B, Jelec R, Vrdoljak S, Plecko T, Nogalo P (2019) Immunophenotyping of a stromal vascular fraction from microfragmented lipoaspirate used in osteoarthritis cartilage treatment and its lipoaspirate counterpart. Genes 10(6):474
Russo A, Screpis D, Di Donato SL, Bonetti S, Piovan G, Zorzi C (2018) Autologous micro-fragmented adipose tissue for the treatment of diffuse degenerative knee osteoarthritis: an update at 3 year follow-up. J Exp Orthop 5(1):52
Gobbi A, Dallo I, Rogers C, Striano RD, Mautner K, Bowers R, Rozak M, Bilbool N, Murrell WD (2021) Two-year clinical outcomes of autologous microfragmented adipose tissue in elderly patients with knee osteoarthritis: a multi-centric, international study. Int Orthop 45(5):1179–1188
Heidari N, Borg T-M, Olgiati S, Slevin M, Danovi A, Fish B, Wilson A, Noorani A (2021) Microfragmented Adipose Tissue Injection (MFAT) may be a solution to the rationing of total knee replacement: a prospective, gender-bias mitigated, reproducible analysis at two years. Stem Cells Int 2021:9921015
Holtz N, Hamilton DF, Giesinger JM, Jost B, Giesinger K (2020) Minimal important differences for the WOMAC osteoarthritis index and the forgotten joint score-12 in total knee arthroplasty patients. BMC Musculoskelet Disord 21(1):401
Clement ND, Bardgett M, Weir D, Holland J, Gerrand C, Deehan DJ (2018) What is the minimum clinically important difference for the WOMAC index after TKA? Clin Orthop Relat Res 476(10):2005
D’Ambrosi R, Indino C, Maccario C, Manzi L, Usuelli FG (2018) Autologous microfractured and purified adipose tissue for arthroscopic management of osteochondral lesions of the talus. J Vis Exp 131:56395
R Core Team (2022) R: a language and environment for statistical computing. Vienna, R Foundation for Statistical Computing. https://www.R-project.org/
Roato I, Belisario DC, Compagno M, Lena A, Bistolfi A, Maccari L, Mussano F, Genova T, Godio L, Perale G, Formica M, Cambieri I, Castagnoli C, Robba T, Felli L, Ferracini R (2019) Concentrated adipose tissue infusion for the treatment of knee osteoarthritis: clinical and histological observations. Int Orthop 43(1):15–23
Spasovski D, Spasovski V, Baščarević Z, Stojiljković M, Vreća M, Anđelković M, Pavlović S (2018) Intra-articular injection of autologous adipose-derived mesenchymal stem cells in the treatment of knee osteoarthritis. J Gene Med 20(1):e3002
Tran TDX, Wu C-M, Dubey NK, Deng Y-H, Su C-W, Pham TT, Le Thi PB, Sestili P, Deng W-P (2019) Time- and kellgren-lawrence grade-dependent changes in intra-articularly transplanted stromal vascular fraction in osteoarthritic patients. Cells 8(4):308
Pers Y-M, Rackwitz L, Ferreira R, Pullig O, Delfour C, Barry F, Sensebe L, Casteilla L, Fleury S, Bourin P, Noël D, Canovas F, Cyteval C, Lisignoli G, Schrauth J, Haddad D, Domergue S, Noeth U, Jorgensen C, on behalf of the ADIPOA Consortium (2016) Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med 5(7):847–856
De Luca P, Kouroupis D, Viganò M, Perucca-Orfei C, Kaplan L, Zagra L, de Girolamo L, Correa D, Colombini A (2019) Human diseased articular cartilage contains a mesenchymal stem cell-like population of chondroprogenitors with strong immunomodulatory responses. J Clin Med 8(4):423
Pagani S, Veronesi F, Giavaresi G, Filardo G, Papio T, Romandini I, Fini M (2021) Autologous protein solution effect on chondrogenic differentiation of mesenchymal stem cells from adipose tissue and bone marrow in an osteoarthritic environment. Cartilage 13(2_suppl):225S-237S
Saldaña L, Bensiamar F, Vallés G, Mancebo FJ, García-Rey E, Vilaboa N (2019) Immunoregulatory potential of mesenchymal stem cells following activation by macrophage-derived soluble factors. Stem Cell Res Ther 10(1):58
Ntege EH, Sunami H, Shimizu Y (2020) Advances in regenerative therapy: A review of the literature and future directions. Regen Ther 14:136–153
Tonnard P, Verpaele A, Peeters G, Hamdi M, Cornelissen M, Declercq H (2013) Nanofat grafting: basic research and clinical applications. Plast Reconstr Surg 132(4):1017–1026
Tremolada C, Colombo V, Ventura C (2016) Adipose tissue and mesenchymal stem cells: state of the art and Lipogems® technology development. Curr Stem Cell Rep 2(3):304–312
Garza JR, Campbell RE, Tjoumakaris FP, Freedman KB, Miller LS, Santa Maria D, Tucker BS (2020) Clinical efficacy of intra-articular mesenchymal stromal cells for the treatment of knee osteoarthritis: a double-blinded prospective randomized controlled clinical trial. Am J Sports Med 48(3):588–598
Freitag J, Bates D, Wickham J, Shah K, Huguenin L, Tenen A, Paterson K, Boyd R (2019) Adipose-derived mesenchymal stem cell therapy in the treatment of knee osteoarthritis: a randomized controlled trial. Regen Med 14(3):213–230
Zaffagnini S, Andriolo L, Boffa A, Poggi A, Cenacchi A, Busacca M, Kon E, Filardo G, Di Martino A (2022) Microfragmented adipose tissue versus platelet-rich plasma for the treatment of knee osteoarthritis: a prospective randomized controlled trial at 2-year follow-up. Am J Sports Med 50(11):2881–2892
Gobbi A, Dallo I, D’Ambrosi R (2022) Autologous microfragmented adipose tissue and leukocyte-poor platelet-rich plasma combined with hyaluronic acid show comparable clinical outcomes for symptomatic early knee osteoarthritis over a two-year follow-up period: a prospective randomized clinical trial. Eur J Orthop Surg Traumatol 33(5):1895–1904
Agarwal N, Mak C, Bojanic C, To K, Khan W (2021) Meta-analysis of adipose tissue derived cell-based therapy for the treatment of knee osteoarthritis. Cells 10(6):1365
Boffa A, Andriolo L, Franceschini M, Martino AD, Asunis E, Grassi A, Zaffagnini S, Filardo G (2021) Minimal clinically important difference and patient acceptable symptom state in patients with knee osteoarthritis treated With PRP injection. Orthop J Sports Med 9(10):23259671211026240
Schiavone Panni A, Vasso M, Braile A, Toro G, De Cicco A, Viggiano D, Lepore F (2019) Preliminary results of autologous adipose-derived stem cells in early knee osteoarthritis: identification of a subpopulation with greater response. Int Orthop 43(1):7–13
Manferdini C, Maumus M, Gabusi E, Piacentini A, Filardo G, Peyrafitte J-A, Jorgensen C, Bourin P, Fleury-Cappellesso S, Facchini A, Noël D, Lisignoli G (2013) Adipose-derived mesenchymal stem cells exert antiinflammatory effects on chondrocytes and synoviocytes from osteoarthritis patients through prostaglandin E2. Arthritis Rheum 65(5):1271–1281
Ortiz-Virumbrales M, Menta R, Pérez LM, Lucchesi O, Mancheño-Corvo P, Avivar-Valderas Á, Palacios I, Herrero-Mendez A, Dalemans W, de la Rosa O, Lombardo E (2020) Human adipose mesenchymal stem cells modulate myeloid cells toward an anti-inflammatory and reparative phenotype: role of IL-6 and PGE2. Stem Cell Res Ther 11(1):462
Zhang Y, Ravikumar M, Ling L, Nurcombe V, Cool SM (2021) Age-related changes in the inflammatory status of human mesenchymal stem cells: implications for cell therapy. Stem Cell Rep 16(4):694–707
Borić I, Hudetz D, Rod E, Jeleč Ž, Vrdoljak T, Skelin A, Polašek O, Plečko M, Trbojević-Akmačić I, Lauc G, Primorac D (2019) A 24-month follow-up study of the effect of intra-articular injection of autologous microfragmented fat tissue on proteoglycan synthesis in patients with knee osteoarthritis. Genes 10(12):1051
Hudetz D, Borić I, Rod E, Jeleč Ž, Radić A, Vrdoljak T, Skelin A, Lauc G, Trbojević-Akmačić I, Plečko M, Polašek O, Primorac D (2017) The effect of intra-articular injection of autologous microfragmented fat tissue on proteoglycan synthesis in patients with knee osteoarthritis. Genes 8(10):270
Dallo I, Szwedowski D, Mobasheri A, Irlandini E, Gobbi A (2021) A prospective study comparing leukocyte-poor platelet-rich plasma combined with hyaluronic acid and autologous microfragmented adipose tissue in patients with early knee osteoarthritis. Stem Cells Dev 30(13):651–659
Previtali D, Merli G, Di G Laura Frattura, Candrian C, Zaffagnini S, Filardo G (2021) The Long-lasting effects of “Placebo Injections” in knee osteoarthritis: a meta-analysis. Cartilage 13(1):185S-196S
Murray IR, Geeslin AG, Goudie EB, Petrigliano FA, LaPrade RF (2017) Minimum Information for Studies Evaluating Biologics in Orthopaedics (MIBO): platelet-rich plasma and mesenchymal stem cells. J Bone Jt Surg 99(10):809–819
We thank the precious figure of Dr Di Donato Sigismondo Luca for his contribution.
Ethics approval and consent to participate
At our institution, for a retrospective study, there is no need for ethical approval.
The authors declare no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Russo, A., Cortina, G., Condello, V. et al. Autologous micro-fragmented adipose tissue injection provides significant and prolonged clinical improvement in patients with knee osteoarthritis: a case-series study. J EXP ORTOP 10, 116 (2023). https://doi.org/10.1186/s40634-023-00668-y