Micro-fragmented adipose tissue injection associated with arthroscopic procedures in patients with symptomatic knee osteoarthritis

Micro-fragmented adipose tissue injection associated with arthroscopic procedures in patients... Background: The social impact of degenerative diseases is steadily increasing, because of the continued rise in the mean age of the active population. Articular cartilage lesions are generally associated with disability and symptoms such as joint pain and reduced function, and remain a challenge for the orthopaedic surgeon. Several non-invasive solution have been proposed, but the results achieved to date are far from being completely satisfactory. Recently, new therapeutic approaches, such as the use of mesenchymal stem cells, have been developed. Among the many sources, the adipose tissue is nowadays considered one of the smartest, due to its abundance and easy access. The aim of this retrospective study is to explore whether patients affected by symptomatic knee osteoarthritis treated with micro-fragmented adipose tissue associated with a chondral shaving procedure experience an improvement in symptoms and function. Methods: Thirty-eight patients affected by symptomatic knee osteoarthritis were treated in 2015 with an arthroscopic procedure associated with an injection of autologous and micro-fragmented adipose tissue. Micro-fragmented adipose tissue was obtained using a minimal manipulation technique in a closed system. Clinical outcomes were determined at 1, 3, 6, and 12 months follow-up using Knee Injury and Osteoarthritis Outcome Score questionnaire and direct physical examination. Safety of the procedure, recording type and incidence of any adverse event, was also assessed. Results: A steady and statistically significant improvement of all the clinical scores from pre-operative evaluation to 1, 3, 6, and 12 months follow-up was observed, with KOOS sport and quality of life being the most improved scores. On average, 92% of the patients clinically improved and 100% of them were satisfied with the treatment. No adverse events nor relevant complications were recorded. Conclusion: The result of the study pointed to micro-fragmented adipose tissue as a safe and beneficial adjuvant in the surgical treatment of degenerative knee chondropathy. The procedure is simple, sustainable, quick, minimally invasive, one-step, and safe. After one year, the results are very satisfactory and promising. A longer follow-up is needed to draw definitive conclusions and enlarge the indications. Trial registration: Registered at clinicaltrials.gov as NCT03527693 on 27 April 2018 (retrospectively registered). Keywords: Knee chondropathy, Osteoarthritis, MSCs, ASCs, Micro-fragmented adipose tissue * Correspondence: gabrielecattaneo@hotmail.com Spotorno Foundation c/o San Michele Clinics, Viale Pontelungo, 79, 17031 Albenga, SV, Italy Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cattaneo et al. BMC Musculoskeletal Disorders (2018) 19:176 Page 2 of 7 Background commercially available technique that intra-operatively The social impact of degenerative diseases such as articu- provides micro-fragmented and minimally manipulated lar cartilage pathology is steadily increasing, because of adipose tissue without expansion or enzymatic treatment the continued rise in the mean age of the active popula- [25] was employed in this study. This approach, that has tion. Articular cartilage lesions are generally, but not been already shown to be safe and promising in different always, associated with disability and with symptoms such pathologies [26–33], provides the key elements to support a as joint pain and reduced function, and might progress to natural reparative response, that is scaffold (the adipose end-stage osteoarthritis (OA). Varieties of non-invasive tissue structure), cells (ASCs), and growth factors (secreted solutions for pain relief, improvement in function and dis- cytokines and chemokines) [34]. The aim of this retrospect- ability, and eventually, modification of the progression of ive study is to explore whether patients affected by symp- severe cartilage lesions and OA, have been proposed with tomatic knee OA treated with micro-fragmented adipose variable success rates [1–3]. Non-surgical treatments, such tissue injection associated with a chondral shaving proced- as physiokinesitherapy, pharmacological treatments (anal- ure experience an improvement in symptoms and function. gesics/anti-inflammatory agents, glucocorticoids, opioids, nonsteroidal anti-inflammatory drugs - NSAIDs), hyalur- Methods onic acid (HA) or its derivatives [4, 5] or platelet-rich Study population plasma (PRP) injections [6, 7], indicated for small or dif- The retrospective analysis of the patient data was ap- fused degenerative lesions, temporarily target the symp- proved by the Regional Ethics Committee of Liguria - toms but cannot prevent the degeneration process [8]. Italy (protocol n° 164REG2016, September 22, 2016). Joint-preserving surgical treatments, such as arthroscopic No approval for the initial treatment of the patients shaving or debridement, laser chondroplasty, and micro- was required being the procedure standard clinical fractures, provide temporary relief of symptoms, but the practice in our Hospital. In 2015, 38 consecutive clinical findings are highly variable and many authors patients affected by symptomatic knee OA underwent contraindicated their use for diffused joint degeneration. an arthroscopic procedure associated with an injec- For these reasons, new therapeutic approaches, such as tion of autologous and micro-fragmented adipose the use of mesenchymal stem cells (MSCs) have been tissue. The indication for the treatment was knee developed. Through trophic, mitogenic, anti-scarring, chondropathy grade > II (ICRS classification), constant anti-apoptotic, immunomodulatory, and anti-microbial pain and failure of conservative treatments (physioki- actions, produced by a large amount of bioactive nesitherapy, corticosteroids, HA and/or PRP) for at elements, growth factors and cytokines, MSCs “sense” and least 12 months. Contraindications for the treatment “signal” changes in the microenvironment where they were immune-mediated (non-infectious) synovitis, OA reside [9, 10]. Bone marrow and adipose tissue are the Kellgren-Lawrence grade > 3, axial defects > 10°, meta- most readily available sources of MSCs, and, in this bolic disorders and BMI > 40. Pre-operative assess- context, the adipose tissue is nowadays considered the ments included standard X-rays, MRI, direct physical smartest due to its abundance, the easy access and the examination, Knee Injury and Osteoarthritis Outcome simple isolation procedure [11, 12]. In addition, of the Score (KOOS) questionnaire. Of these 38 patients, 3 many cell types contained in the adipose tissue, MSCs subjects were treated with micro-perforations because (ASCs) comprise up to 2%, whereas only 0.02% of cells in of a severe chondral damage and where excluded bone marrow are MSCs. The use of ASCs, either from the global analysis. The remaining 35 underwent culture-expanded or obtained by mechanical or enzymatic a standard chondral shaving procedure [35]. Those treatment as stromal vascular fraction (SVF) [13]have patients having also a meniscal injury no longer re- recently created a huge interest in the context of cartilage pairable (14 patients) underwent an associated men- regeneration and shown promising results [14–18]. How- iscectomy to correct the defect. ever, 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 Harvesting of the adipose tissue addition to the large number of processing steps, the high The lower or the lateral abdomen was chosen as donor economic burden, and the restrictions associated with cell site for adipose tissue harvesting. Before harvesting the expansion and extensive manipulation [22, 23], the results fat, the site was injected with Klein solution (1 vial 3 3 achieved to date are far from being completely satisfactory. adrenaline + 50 cm mepivacaine 2% in 250 cm saline) Therefore, availability of a minimally manipulated adipose using a disposable 17G blunt cannula connected to a tissue providing in one-step the key elements to support a luer-lock 60-cm syringe. The fat was then harvested natural regenerative response would have remarkable using a 13G blunt cannula, for a fast and a-traumatic clinical relevance [24]. Based on these considerations, a suction, connected to a VacLok® 20-ml syringe. Cattaneo et al. BMC Musculoskeletal Disorders (2018) 19:176 Page 3 of 7 Processing of the adipose tissue with Lipogems® device Results and injection in the joint Due to the differences in the surgical procedure, the The harvested fat was immediately processed in the Lipo- patients that underwent the corrective meniscectomy gems® processing kit, a disposable device that progressively were analysed separately and indicated in the text with reduces the size of the adipose tissue clusters while the code “SM”; patients that underwent the chondral eliminating oily substances and blood residues with shaving only are indicated with the code “SH”. Back- pro-inflammatory properties. The entire process, carried ground data of the two sub-populations included in the out in one surgical step, was performed in complete study are reported in Table 1. immersion in physiological solution minimizing any The analysis of the SH category data revealed a steady trauma to the cells. The resulting micro-fragmented fat and statistically significant improvement of all the clin- was collected in a 60-cm syringe and positioned for ical scores from pre-operative evaluation to 1, 3, 6, and decanting the excess saline solution. The resulting product 12 months follow-up (Fig. 1a). At 12 months, the aver- was then transferred into several 10-cm syringes to be age improvement in KOOS compared to pre-operative injected in the patient. Micro-fragmented fat (10 cm ) was condition was 29 in symptoms (p < 0.0001), 36 in pain injected intra-articular after the arthroscopic procedure (p < 0.0001), 37 in function in daily living (p < 0.0001), 51 (shaving or shaving + meniscectomy). Table 1 Characteristics of the 2 study populations SH group MS group Post-op rehabilitation protocol and clinical evaluations Age All patients were discharged the day after the procedure with an elastic compression band on the harvesting site, Mean 53 y.o. 55 y.o. low MW heparin for 3 weeks, 2 weeks of unloading and SD 12 11 then full load recovery in the following 7 days. Continu- Gender ous passive motion from the immediate post-op and M 13 (62%) 8 (57%) active physiokinesitherapy from day 15 post-op. F 8 (38%) 6 (43%) Standard clinical evaluations at 1, 3, 6, and 12 months BMI post-op included Knee Injury and Osteoarthritis Out- come Score (KOOS) questionnaire and direct physical Mean 27 27 examination with the evaluation of knee range of mo- SD 4 4 tion, patellar subluxation, ability to walk, go up and Smoke down the stairs, squatting, muscular strength, stiffness Smokers/Former 8 (38%) 5 (36%) and knee swelling. The Western Ontario and McMaster Non Smokers 13 (62%) 9 (64%) Universities Osteoarthritis Index (WOMAC) was calcu- Grade Chondropathy lated from the KOOS. (ICRS classification) II 5 (24%) 2 (14%) Safety assessment III 8 (38%) 7 (50%) Safety was assessed by evaluating local adverse events, IV 8 (38%) 5 (36%) such as infections, fever, and excessive swelling of the Grade OA knee at 1, 3, 6, and 12 months post-op. (Kellgren Lawrence) 1 8 (38%) 1 (7%) Statistical analysis 2 4 (19%) 2 (14%) To guarantee standard operating procedures, all the 3 9 (43%) 11 (79%) patients were operated by the same surgeon (GC) and the clinical evaluations at any follow-up time were performed Site of Lesion by the same surgeon assisted by another surgeon. Consid- FC 10 (48%) 11 (79%) ering the relatively small sample size, results are expressed PF 3 (14%) 3 (21%) as the mean and standard deviation. For statistical com- TP 8 (38%) – parisons, the chi-squared test for all categorical data, Type of Lesion Student’s t-test for unpaired groups for parametric data, Diffused 16 (76%) 11 (79%) and Mann-Whitney test for non-parametric data (calcu- lated with the Kolmogorov-Smirnoff normality test) were Focal - mean size 5 (24%) - 10 mm 3 (21%) - 14 mm used (GraphPad Prism v5.0, La Jolla, USA). A p < 0.05 was Surgery SH SM considered statistically significant. A p < 0.1 is reported as SD standard deviation, FC femoral condyle, PF patellofemoral, TP tibial plateau, atendency. SH chondral shaving, SM chondral shaving + meniscectomy Cattaneo et al. BMC Musculoskeletal Disorders (2018) 19:176 Page 4 of 7 ab Fig. 1 Trend of functional improvements of the SH group from baseline to 12 months’ follow-up. Results are expressed as mean and standard error. A p < 0.05 (T12 vs. T0) was considered statistically significant (# #). a KOOS score. KOOS S = symptoms; KOOS P = pain; KOOS ADL = activity daily living; KOOS Spt = sport; KOOS QoL = quality of life. b WOMAC Index in sport (p < 0.0001) and 54 in the quality of life (p < KOOS symptoms 17 vs. 29 [p≅0.05], pain 12 vs. 36 t12-t0 0.0001). Statistically significant differences (p < 0.0001) [p < 0.05], function in daily living 16 vs. 37 [p < 0.05], sport between pre-treatment and follow-up values were found 24 vs. 51 [p < 0.05], and quality of life 26 vs. 54 [p <0.01]). also for the total WOMAC scores. In details, pain, stiff- Interestingly, despite this finding, the Student’s t-test ness and functional limitation decreased from an average revealed that, besides the meniscectomy, other parameters of 43 at baseline to 30 at 1 month, 24 at 3 months, 18 at such as age, sex, type and grade of chondropathy affect 6 months, and 8 at 12 months (Fig. 1b). The physical specific outcomes at different time points. Due to the examination at 6 months revealed that the majority of small number of patients, this analysis has been performed the patients entered in the category “normal” and, at on the whole population (35 patients). At 1 month, 12 months, no patients were in the category “symptom- women and patients under 55 years old showed better atic” except for one patient in squatting (see Table 2 for improvements in the KOOS sport compared to men and comparison with the pre-operative condition). elderly patients respectively (31% women vs. 14% men [p Results of the SM population appeared slightly different, < 0.05] and 30% patients < 55 y.o. vs. 9% patients > 55 y.o. with a steady and statistically significant improvement of [p < 0.01]). At 3 months, patients with a chondropathy of all the clinical scores until the 6 months follow-up grade IV showed higher improvements in the KOOS qual- followed by a slight, but not statistically significant, de- ity of life compared to patients with a grade II-III (51% crease at 12 months (Fig. 2a). At 12 months, the average grade IV vs. 31% grade II-III, p≅0.05). In addition, patients improvement in KOOS compared to pre-operative condi- with a femoral condyle chondropathy showed better im- tion was 17 in symptoms (p = 0.014), 12 in pain (p = provements in the KOOS pain compared to patients af- 0.183), 16 in function in daily living (p = 0.027), 24 in sport fected by a patellofemoral chondropathy (31% femoral (p = 0.014) and 26 in the quality of life (p =0.002). The condyle vs. 11% patellofemoral, p≅0.05). At 6 months, pa- same trend was found between pre-treatment and tients under 55 years old showed better improvements in follow-up values for the total WOMAC scores (p < the KOOS sport compared to elderly patients (41% vs. 0.0001). In details, pain, stiffness and functional limitation 23% respectively, p < 0.05). At 12 months, only the surgi- decreased from an average of 40 at baseline to 24 at cal procedure (meniscectomy), as already shown, affects 1 month, 20 at 3 months, 17 at 6 months, and 24 at the outcomes. Considering the improvement between the 12 months (Fig. 2b). The physical examination at 6 months pre-operative scores and the last follow up at 12 months, revealed that the majority of the patients entered in the females showed better improvements in KOOS functional category “normal” and, at 12 months, no patients were in score with respect to males (tendency, p =0.077). the category “symptomatic” except for one patient in Interestingly, the degree of OA does not significantly walking and two patients in squatting (see Table 2 for affect the outcomes. comparison with pre-operative condition). The compari- On average, 92% of the SH patients and 74% of the son of the two populations revealed that SM patients im- SM patients clinically improved (Table 3) and 100% of proved less, but still a lot, compared to SH patients (Δ them were satisfied with the treatment. Cattaneo et al. BMC Musculoskeletal Disorders (2018) 19:176 Page 5 of 7 Table 2 Knee objective evaluation – summary of the results ROM PAT SUBLUX Walking Stairs Squatting Strength Stiffness Swelling SH Pre-op N 43% 86% 76% 71% 5% 90% 95% 57% S 57% 14% 24% 29% 95% 10% 5% 43% 6 months N 100% 100% 100% 100% 71% 100% 100% 100% S 0% 0% 0% 0% 29% 0% 0% 0% 12 months N 100% 100% 100% 100% 95% 100% 100% 100% S0% 0% 0% 0% 5% 0% 0% 0% MS Pre-op N 36% 100% 86% 43% 0% 100% 100% 36% S 64% 0% 14% 57% 100% 0% 0% 64% 6 months N 100% 100% 100% 92% 77% 100% 100% 100% S 0% 0% 0% 8% 23% 0% 0% 0% 12 months N 100% 100% 93% 100% 86% 100% 100% 100% S 0% 0% 7% 0% 14% 0% 0% 0% N normal, S symptomatic, ROM range of motion, PAT SUBLUX patellar subluxation No adverse events or complications were observed adipose tissue injection (data not shown). At 12 months, throughout the follow-up period, apart from one case of a the average improvement for KOOS was 46 in symptoms temporary and small subcutaneous hematoma that did (p < 0.0001), 48 in pain (p < 0.0001), 41 in function in daily not require any additional treatment. For the sake of com- living (p < 0.0001), 28 in sport (p < 0.0001) and 25 in the prehensiveness, we report also the exceptional outcomes quality of life (p < 0.0001). Statistically significant differ- of the three patients (ICRS grade III-IV) that underwent ences (p < 0.0001) between pre-treatment and follow-up the micro-perforations associated with micro-fragmented values were found also for the total WOMAC scores ab Fig. 2 Trend of functional improvements of the SM group from baseline to 12 months’ follow-up. Results are expressed as mean and standard error. A p < 0.05 (T12 vs. T0) was considered statistically significant (# #). a KOOS score. KOOS S = symptoms; KOOS P = pain; KOOS ADL = activity daily living; KOOS Spt = sport; KOOS QoL = quality of life. b WOMAC Index Cattaneo et al. BMC Musculoskeletal Disorders (2018) 19:176 Page 6 of 7 Table 3 Summary of the results Δ KOOS_s Δ KOOS_p Δ KOOS_adl Δ KOOS_spt Δ KOOS_QoL Δ WOMAC SH Mean 29 36 37 51 54 −36 SE 1.11 1.45 1.31 1.73 1.32 1.31 % improved patients 90% 86% 95% 90% 95% 95% SM Mean 17 12 16 24 26 −15 SE 2.2 2.4 1.7 2.7 1.7 1.8 % improved patients 64% 57% 86% 71% 86% 79% Data are expressed as mean Δ (t -t ) and standard error (SE) 12 0 SH chondral shaving, SM chondral shaving + meniscectomy, s symptoms, p pain, adl function in daily living, spt sport, QoL quality of life where the pain, stiffness and functional limitation de- follow-up, is that no patient worsened compared to the creased from 56 at baseline to 12 at 12 months follow-up. pre-operative condition or underwent additional treat- ments. Noteworthy, patients who declared to be very Discussion active in sport still improved, demonstrating that also This study retrospectively analysed the safety and poten- high functional demands benefit from the treatment tial benefits of using autologous and micro-fragmented (data not shown). The meniscectomy did not substan- adipose tissue as adjuvant in the surgical treatment of tially affected the outcomes that were, anyway, very degenerative knee chondropathy. The results demon- positive, with an average improvements of all the strated that, when associated with a shaving procedure, KOOS scores of 20 points and a physical examination it improves symptoms and function at least until 1-year positive for all the patients except for 2 in squatting. follow-up, with a trend of steady increase during time. This is a very important finding, considering reported Indeed, a constant and statistically significant improve- data showing that meniscectomy in the long term has ment of all the clinical scores was observed from pre-op been shown both experimentally and clinically to ex- evaluation to the 1, 3, 6, and 12 months follow-up with acerbate the osteoarthritic condition [1]. The observed KOOS sport and quality of life being the most improved decrease in the scores from 6 to 12 months, although scores. not statistically significant, can be explained by a loss of Articular cartilage lesions and degenerations, gener- the functional unit “meniscus” in terms of knee stability ally associated with disability and symptoms such as leading to a progressive chondral damage. Nevertheless, joint pain and reduced function, are hard to treat and the MRI at 12 months revealed no signs of bone edema remain challenging. Current pharmacologic interven- in the treated compartments as index of severe chon- tions only temporarily reduce pain and symptoms, dral damage. The main limitation of the study is the but no proven disease-modifying therapy is available lack of a control group that does not allow for any de- [1]. Non-surgical treatments, such as HA or PRP finitive conclusion about micro-fragmented adipose tis- injections target the symptoms but cannot inhibit the sue effect. Nevertheless, we believe that this approach degeneration process. Joint-preserving surgical treat- is very promising since, in our experience, standard ments, such as arthroscopic shaving, debridement, chondral shaving did not allow for satisfactory results laser chondroplasty, and microfractures, provide tem- so far. porary relief of symptoms, but for the diffused degen- erative pathology or chondropathies at the initial stage are contraindicated by many authors. In these Conclusion cases, regenerative medicine, and, in particular, the The results of this study show the safety and potential use of progenitor cells is preferable. Indeed, besides benefits of using autologous, micro-fragmented and their multipotency, these cells secrete a variety of minimally manipulated adipose tissue injection associated bioactive molecules that act in a paracrine manner to with the arthroscopic chondral shaving for the treatment prime and sustain angiogenic, anti-fibrotic, anti-apoptotic, of diffused knee chondropathy. The procedure is simple, anti-microbial and immunomodulatory responses in the sustainable, quick, minimally invasive, one-step, and safe. target tissue [9, 11, 36]. After one year, the results are very satisfactory and prom- A very important finding of this study, in addition to ising. A longer follow-up and a randomized controlled the constant improvement of all the clinical scores study on a big number of patients is needed to draw from baseline evaluation to the 1, 3, 6, and 12 months definitive conclusions and enlarge the indications. Cattaneo et al. BMC Musculoskeletal Disorders (2018) 19:176 Page 7 of 7 Abbreviations 11. Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of ASCs: Adipose-derived stem cells; FC: Femoral condyle; HA: Hyaluronic acid; multipotent stem cells. Mol Biol Cell. 2002;13:4279–95. KOOS: Knee Injury and Osteoarthritis Outcome Score; MSCs: Mesenchymal 12. Gimble JM, Guilak F, Bunnell BA. Clinical and preclinical translation of cell- stem cells; NSAIDs: Nonsteroidal anti-inflammatory drugs; OA: Osteoarthritis; based therapies using adipose tissue-derived cells. Stem Cell Res Ther. 2010;1:1. PF: Patellofemoral; PRP: Platelet-rich plasma; SVF: Stromal vascular fraction; 13. Aronowitz JA, Lockhart RA, Hakakian CS. 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Micro-fragmented adipose tissue injection associated with arthroscopic procedures in patients with symptomatic knee osteoarthritis

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Medicine & Public Health; Orthopedics; Rehabilitation; Rheumatology; Sports Medicine; Internal Medicine; Epidemiology
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Abstract

Background: The social impact of degenerative diseases is steadily increasing, because of the continued rise in the mean age of the active population. Articular cartilage lesions are generally associated with disability and symptoms such as joint pain and reduced function, and remain a challenge for the orthopaedic surgeon. Several non-invasive solution have been proposed, but the results achieved to date are far from being completely satisfactory. Recently, new therapeutic approaches, such as the use of mesenchymal stem cells, have been developed. Among the many sources, the adipose tissue is nowadays considered one of the smartest, due to its abundance and easy access. The aim of this retrospective study is to explore whether patients affected by symptomatic knee osteoarthritis treated with micro-fragmented adipose tissue associated with a chondral shaving procedure experience an improvement in symptoms and function. Methods: Thirty-eight patients affected by symptomatic knee osteoarthritis were treated in 2015 with an arthroscopic procedure associated with an injection of autologous and micro-fragmented adipose tissue. Micro-fragmented adipose tissue was obtained using a minimal manipulation technique in a closed system. Clinical outcomes were determined at 1, 3, 6, and 12 months follow-up using Knee Injury and Osteoarthritis Outcome Score questionnaire and direct physical examination. Safety of the procedure, recording type and incidence of any adverse event, was also assessed. Results: A steady and statistically significant improvement of all the clinical scores from pre-operative evaluation to 1, 3, 6, and 12 months follow-up was observed, with KOOS sport and quality of life being the most improved scores. On average, 92% of the patients clinically improved and 100% of them were satisfied with the treatment. No adverse events nor relevant complications were recorded. Conclusion: The result of the study pointed to micro-fragmented adipose tissue as a safe and beneficial adjuvant in the surgical treatment of degenerative knee chondropathy. The procedure is simple, sustainable, quick, minimally invasive, one-step, and safe. After one year, the results are very satisfactory and promising. A longer follow-up is needed to draw definitive conclusions and enlarge the indications. Trial registration: Registered at clinicaltrials.gov as NCT03527693 on 27 April 2018 (retrospectively registered). Keywords: Knee chondropathy, Osteoarthritis, MSCs, ASCs, Micro-fragmented adipose tissue * Correspondence: gabrielecattaneo@hotmail.com Spotorno Foundation c/o San Michele Clinics, Viale Pontelungo, 79, 17031 Albenga, SV, Italy Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cattaneo et al. BMC Musculoskeletal Disorders (2018) 19:176 Page 2 of 7 Background commercially available technique that intra-operatively The social impact of degenerative diseases such as articu- provides micro-fragmented and minimally manipulated lar cartilage pathology is steadily increasing, because of adipose tissue without expansion or enzymatic treatment the continued rise in the mean age of the active popula- [25] was employed in this study. This approach, that has tion. Articular cartilage lesions are generally, but not been already shown to be safe and promising in different always, associated with disability and with symptoms such pathologies [26–33], provides the key elements to support a as joint pain and reduced function, and might progress to natural reparative response, that is scaffold (the adipose end-stage osteoarthritis (OA). Varieties of non-invasive tissue structure), cells (ASCs), and growth factors (secreted solutions for pain relief, improvement in function and dis- cytokines and chemokines) [34]. The aim of this retrospect- ability, and eventually, modification of the progression of ive study is to explore whether patients affected by symp- severe cartilage lesions and OA, have been proposed with tomatic knee OA treated with micro-fragmented adipose variable success rates [1–3]. Non-surgical treatments, such tissue injection associated with a chondral shaving proced- as physiokinesitherapy, pharmacological treatments (anal- ure experience an improvement in symptoms and function. gesics/anti-inflammatory agents, glucocorticoids, opioids, nonsteroidal anti-inflammatory drugs - NSAIDs), hyalur- Methods onic acid (HA) or its derivatives [4, 5] or platelet-rich Study population plasma (PRP) injections [6, 7], indicated for small or dif- The retrospective analysis of the patient data was ap- fused degenerative lesions, temporarily target the symp- proved by the Regional Ethics Committee of Liguria - toms but cannot prevent the degeneration process [8]. Italy (protocol n° 164REG2016, September 22, 2016). Joint-preserving surgical treatments, such as arthroscopic No approval for the initial treatment of the patients shaving or debridement, laser chondroplasty, and micro- was required being the procedure standard clinical fractures, provide temporary relief of symptoms, but the practice in our Hospital. In 2015, 38 consecutive clinical findings are highly variable and many authors patients affected by symptomatic knee OA underwent contraindicated their use for diffused joint degeneration. an arthroscopic procedure associated with an injec- For these reasons, new therapeutic approaches, such as tion of autologous and micro-fragmented adipose the use of mesenchymal stem cells (MSCs) have been tissue. The indication for the treatment was knee developed. Through trophic, mitogenic, anti-scarring, chondropathy grade > II (ICRS classification), constant anti-apoptotic, immunomodulatory, and anti-microbial pain and failure of conservative treatments (physioki- actions, produced by a large amount of bioactive nesitherapy, corticosteroids, HA and/or PRP) for at elements, growth factors and cytokines, MSCs “sense” and least 12 months. Contraindications for the treatment “signal” changes in the microenvironment where they were immune-mediated (non-infectious) synovitis, OA reside [9, 10]. Bone marrow and adipose tissue are the Kellgren-Lawrence grade > 3, axial defects > 10°, meta- most readily available sources of MSCs, and, in this bolic disorders and BMI > 40. Pre-operative assess- context, the adipose tissue is nowadays considered the ments included standard X-rays, MRI, direct physical smartest due to its abundance, the easy access and the examination, Knee Injury and Osteoarthritis Outcome simple isolation procedure [11, 12]. In addition, of the Score (KOOS) questionnaire. Of these 38 patients, 3 many cell types contained in the adipose tissue, MSCs subjects were treated with micro-perforations because (ASCs) comprise up to 2%, whereas only 0.02% of cells in of a severe chondral damage and where excluded bone marrow are MSCs. The use of ASCs, either from the global analysis. The remaining 35 underwent culture-expanded or obtained by mechanical or enzymatic a standard chondral shaving procedure [35]. Those treatment as stromal vascular fraction (SVF) [13]have patients having also a meniscal injury no longer re- recently created a huge interest in the context of cartilage pairable (14 patients) underwent an associated men- regeneration and shown promising results [14–18]. How- iscectomy to correct the defect. ever, 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 Harvesting of the adipose tissue addition to the large number of processing steps, the high The lower or the lateral abdomen was chosen as donor economic burden, and the restrictions associated with cell site for adipose tissue harvesting. Before harvesting the expansion and extensive manipulation [22, 23], the results fat, the site was injected with Klein solution (1 vial 3 3 achieved to date are far from being completely satisfactory. adrenaline + 50 cm mepivacaine 2% in 250 cm saline) Therefore, availability of a minimally manipulated adipose using a disposable 17G blunt cannula connected to a tissue providing in one-step the key elements to support a luer-lock 60-cm syringe. The fat was then harvested natural regenerative response would have remarkable using a 13G blunt cannula, for a fast and a-traumatic clinical relevance [24]. Based on these considerations, a suction, connected to a VacLok® 20-ml syringe. Cattaneo et al. BMC Musculoskeletal Disorders (2018) 19:176 Page 3 of 7 Processing of the adipose tissue with Lipogems® device Results and injection in the joint Due to the differences in the surgical procedure, the The harvested fat was immediately processed in the Lipo- patients that underwent the corrective meniscectomy gems® processing kit, a disposable device that progressively were analysed separately and indicated in the text with reduces the size of the adipose tissue clusters while the code “SM”; patients that underwent the chondral eliminating oily substances and blood residues with shaving only are indicated with the code “SH”. Back- pro-inflammatory properties. The entire process, carried ground data of the two sub-populations included in the out in one surgical step, was performed in complete study are reported in Table 1. immersion in physiological solution minimizing any The analysis of the SH category data revealed a steady trauma to the cells. The resulting micro-fragmented fat and statistically significant improvement of all the clin- was collected in a 60-cm syringe and positioned for ical scores from pre-operative evaluation to 1, 3, 6, and decanting the excess saline solution. The resulting product 12 months follow-up (Fig. 1a). At 12 months, the aver- was then transferred into several 10-cm syringes to be age improvement in KOOS compared to pre-operative injected in the patient. Micro-fragmented fat (10 cm ) was condition was 29 in symptoms (p < 0.0001), 36 in pain injected intra-articular after the arthroscopic procedure (p < 0.0001), 37 in function in daily living (p < 0.0001), 51 (shaving or shaving + meniscectomy). Table 1 Characteristics of the 2 study populations SH group MS group Post-op rehabilitation protocol and clinical evaluations Age All patients were discharged the day after the procedure with an elastic compression band on the harvesting site, Mean 53 y.o. 55 y.o. low MW heparin for 3 weeks, 2 weeks of unloading and SD 12 11 then full load recovery in the following 7 days. Continu- Gender ous passive motion from the immediate post-op and M 13 (62%) 8 (57%) active physiokinesitherapy from day 15 post-op. F 8 (38%) 6 (43%) Standard clinical evaluations at 1, 3, 6, and 12 months BMI post-op included Knee Injury and Osteoarthritis Out- come Score (KOOS) questionnaire and direct physical Mean 27 27 examination with the evaluation of knee range of mo- SD 4 4 tion, patellar subluxation, ability to walk, go up and Smoke down the stairs, squatting, muscular strength, stiffness Smokers/Former 8 (38%) 5 (36%) and knee swelling. The Western Ontario and McMaster Non Smokers 13 (62%) 9 (64%) Universities Osteoarthritis Index (WOMAC) was calcu- Grade Chondropathy lated from the KOOS. (ICRS classification) II 5 (24%) 2 (14%) Safety assessment III 8 (38%) 7 (50%) Safety was assessed by evaluating local adverse events, IV 8 (38%) 5 (36%) such as infections, fever, and excessive swelling of the Grade OA knee at 1, 3, 6, and 12 months post-op. (Kellgren Lawrence) 1 8 (38%) 1 (7%) Statistical analysis 2 4 (19%) 2 (14%) To guarantee standard operating procedures, all the 3 9 (43%) 11 (79%) patients were operated by the same surgeon (GC) and the clinical evaluations at any follow-up time were performed Site of Lesion by the same surgeon assisted by another surgeon. Consid- FC 10 (48%) 11 (79%) ering the relatively small sample size, results are expressed PF 3 (14%) 3 (21%) as the mean and standard deviation. For statistical com- TP 8 (38%) – parisons, the chi-squared test for all categorical data, Type of Lesion Student’s t-test for unpaired groups for parametric data, Diffused 16 (76%) 11 (79%) and Mann-Whitney test for non-parametric data (calcu- lated with the Kolmogorov-Smirnoff normality test) were Focal - mean size 5 (24%) - 10 mm 3 (21%) - 14 mm used (GraphPad Prism v5.0, La Jolla, USA). A p < 0.05 was Surgery SH SM considered statistically significant. A p < 0.1 is reported as SD standard deviation, FC femoral condyle, PF patellofemoral, TP tibial plateau, atendency. SH chondral shaving, SM chondral shaving + meniscectomy Cattaneo et al. BMC Musculoskeletal Disorders (2018) 19:176 Page 4 of 7 ab Fig. 1 Trend of functional improvements of the SH group from baseline to 12 months’ follow-up. Results are expressed as mean and standard error. A p < 0.05 (T12 vs. T0) was considered statistically significant (# #). a KOOS score. KOOS S = symptoms; KOOS P = pain; KOOS ADL = activity daily living; KOOS Spt = sport; KOOS QoL = quality of life. b WOMAC Index in sport (p < 0.0001) and 54 in the quality of life (p < KOOS symptoms 17 vs. 29 [p≅0.05], pain 12 vs. 36 t12-t0 0.0001). Statistically significant differences (p < 0.0001) [p < 0.05], function in daily living 16 vs. 37 [p < 0.05], sport between pre-treatment and follow-up values were found 24 vs. 51 [p < 0.05], and quality of life 26 vs. 54 [p <0.01]). also for the total WOMAC scores. In details, pain, stiff- Interestingly, despite this finding, the Student’s t-test ness and functional limitation decreased from an average revealed that, besides the meniscectomy, other parameters of 43 at baseline to 30 at 1 month, 24 at 3 months, 18 at such as age, sex, type and grade of chondropathy affect 6 months, and 8 at 12 months (Fig. 1b). The physical specific outcomes at different time points. Due to the examination at 6 months revealed that the majority of small number of patients, this analysis has been performed the patients entered in the category “normal” and, at on the whole population (35 patients). At 1 month, 12 months, no patients were in the category “symptom- women and patients under 55 years old showed better atic” except for one patient in squatting (see Table 2 for improvements in the KOOS sport compared to men and comparison with the pre-operative condition). elderly patients respectively (31% women vs. 14% men [p Results of the SM population appeared slightly different, < 0.05] and 30% patients < 55 y.o. vs. 9% patients > 55 y.o. with a steady and statistically significant improvement of [p < 0.01]). At 3 months, patients with a chondropathy of all the clinical scores until the 6 months follow-up grade IV showed higher improvements in the KOOS qual- followed by a slight, but not statistically significant, de- ity of life compared to patients with a grade II-III (51% crease at 12 months (Fig. 2a). At 12 months, the average grade IV vs. 31% grade II-III, p≅0.05). In addition, patients improvement in KOOS compared to pre-operative condi- with a femoral condyle chondropathy showed better im- tion was 17 in symptoms (p = 0.014), 12 in pain (p = provements in the KOOS pain compared to patients af- 0.183), 16 in function in daily living (p = 0.027), 24 in sport fected by a patellofemoral chondropathy (31% femoral (p = 0.014) and 26 in the quality of life (p =0.002). The condyle vs. 11% patellofemoral, p≅0.05). At 6 months, pa- same trend was found between pre-treatment and tients under 55 years old showed better improvements in follow-up values for the total WOMAC scores (p < the KOOS sport compared to elderly patients (41% vs. 0.0001). In details, pain, stiffness and functional limitation 23% respectively, p < 0.05). At 12 months, only the surgi- decreased from an average of 40 at baseline to 24 at cal procedure (meniscectomy), as already shown, affects 1 month, 20 at 3 months, 17 at 6 months, and 24 at the outcomes. Considering the improvement between the 12 months (Fig. 2b). The physical examination at 6 months pre-operative scores and the last follow up at 12 months, revealed that the majority of the patients entered in the females showed better improvements in KOOS functional category “normal” and, at 12 months, no patients were in score with respect to males (tendency, p =0.077). the category “symptomatic” except for one patient in Interestingly, the degree of OA does not significantly walking and two patients in squatting (see Table 2 for affect the outcomes. comparison with pre-operative condition). The compari- On average, 92% of the SH patients and 74% of the son of the two populations revealed that SM patients im- SM patients clinically improved (Table 3) and 100% of proved less, but still a lot, compared to SH patients (Δ them were satisfied with the treatment. Cattaneo et al. BMC Musculoskeletal Disorders (2018) 19:176 Page 5 of 7 Table 2 Knee objective evaluation – summary of the results ROM PAT SUBLUX Walking Stairs Squatting Strength Stiffness Swelling SH Pre-op N 43% 86% 76% 71% 5% 90% 95% 57% S 57% 14% 24% 29% 95% 10% 5% 43% 6 months N 100% 100% 100% 100% 71% 100% 100% 100% S 0% 0% 0% 0% 29% 0% 0% 0% 12 months N 100% 100% 100% 100% 95% 100% 100% 100% S0% 0% 0% 0% 5% 0% 0% 0% MS Pre-op N 36% 100% 86% 43% 0% 100% 100% 36% S 64% 0% 14% 57% 100% 0% 0% 64% 6 months N 100% 100% 100% 92% 77% 100% 100% 100% S 0% 0% 0% 8% 23% 0% 0% 0% 12 months N 100% 100% 93% 100% 86% 100% 100% 100% S 0% 0% 7% 0% 14% 0% 0% 0% N normal, S symptomatic, ROM range of motion, PAT SUBLUX patellar subluxation No adverse events or complications were observed adipose tissue injection (data not shown). At 12 months, throughout the follow-up period, apart from one case of a the average improvement for KOOS was 46 in symptoms temporary and small subcutaneous hematoma that did (p < 0.0001), 48 in pain (p < 0.0001), 41 in function in daily not require any additional treatment. For the sake of com- living (p < 0.0001), 28 in sport (p < 0.0001) and 25 in the prehensiveness, we report also the exceptional outcomes quality of life (p < 0.0001). Statistically significant differ- of the three patients (ICRS grade III-IV) that underwent ences (p < 0.0001) between pre-treatment and follow-up the micro-perforations associated with micro-fragmented values were found also for the total WOMAC scores ab Fig. 2 Trend of functional improvements of the SM group from baseline to 12 months’ follow-up. Results are expressed as mean and standard error. A p < 0.05 (T12 vs. T0) was considered statistically significant (# #). a KOOS score. KOOS S = symptoms; KOOS P = pain; KOOS ADL = activity daily living; KOOS Spt = sport; KOOS QoL = quality of life. b WOMAC Index Cattaneo et al. BMC Musculoskeletal Disorders (2018) 19:176 Page 6 of 7 Table 3 Summary of the results Δ KOOS_s Δ KOOS_p Δ KOOS_adl Δ KOOS_spt Δ KOOS_QoL Δ WOMAC SH Mean 29 36 37 51 54 −36 SE 1.11 1.45 1.31 1.73 1.32 1.31 % improved patients 90% 86% 95% 90% 95% 95% SM Mean 17 12 16 24 26 −15 SE 2.2 2.4 1.7 2.7 1.7 1.8 % improved patients 64% 57% 86% 71% 86% 79% Data are expressed as mean Δ (t -t ) and standard error (SE) 12 0 SH chondral shaving, SM chondral shaving + meniscectomy, s symptoms, p pain, adl function in daily living, spt sport, QoL quality of life where the pain, stiffness and functional limitation de- follow-up, is that no patient worsened compared to the creased from 56 at baseline to 12 at 12 months follow-up. pre-operative condition or underwent additional treat- ments. Noteworthy, patients who declared to be very Discussion active in sport still improved, demonstrating that also This study retrospectively analysed the safety and poten- high functional demands benefit from the treatment tial benefits of using autologous and micro-fragmented (data not shown). The meniscectomy did not substan- adipose tissue as adjuvant in the surgical treatment of tially affected the outcomes that were, anyway, very degenerative knee chondropathy. The results demon- positive, with an average improvements of all the strated that, when associated with a shaving procedure, KOOS scores of 20 points and a physical examination it improves symptoms and function at least until 1-year positive for all the patients except for 2 in squatting. follow-up, with a trend of steady increase during time. This is a very important finding, considering reported Indeed, a constant and statistically significant improve- data showing that meniscectomy in the long term has ment of all the clinical scores was observed from pre-op been shown both experimentally and clinically to ex- evaluation to the 1, 3, 6, and 12 months follow-up with acerbate the osteoarthritic condition [1]. The observed KOOS sport and quality of life being the most improved decrease in the scores from 6 to 12 months, although scores. not statistically significant, can be explained by a loss of Articular cartilage lesions and degenerations, gener- the functional unit “meniscus” in terms of knee stability ally associated with disability and symptoms such as leading to a progressive chondral damage. Nevertheless, joint pain and reduced function, are hard to treat and the MRI at 12 months revealed no signs of bone edema remain challenging. Current pharmacologic interven- in the treated compartments as index of severe chon- tions only temporarily reduce pain and symptoms, dral damage. The main limitation of the study is the but no proven disease-modifying therapy is available lack of a control group that does not allow for any de- [1]. Non-surgical treatments, such as HA or PRP finitive conclusion about micro-fragmented adipose tis- injections target the symptoms but cannot inhibit the sue effect. Nevertheless, we believe that this approach degeneration process. Joint-preserving surgical treat- is very promising since, in our experience, standard ments, such as arthroscopic shaving, debridement, chondral shaving did not allow for satisfactory results laser chondroplasty, and microfractures, provide tem- so far. porary relief of symptoms, but for the diffused degen- erative pathology or chondropathies at the initial stage are contraindicated by many authors. In these Conclusion cases, regenerative medicine, and, in particular, the The results of this study show the safety and potential use of progenitor cells is preferable. Indeed, besides benefits of using autologous, micro-fragmented and their multipotency, these cells secrete a variety of minimally manipulated adipose tissue injection associated bioactive molecules that act in a paracrine manner to with the arthroscopic chondral shaving for the treatment prime and sustain angiogenic, anti-fibrotic, anti-apoptotic, of diffused knee chondropathy. The procedure is simple, anti-microbial and immunomodulatory responses in the sustainable, quick, minimally invasive, one-step, and safe. target tissue [9, 11, 36]. After one year, the results are very satisfactory and prom- A very important finding of this study, in addition to ising. A longer follow-up and a randomized controlled the constant improvement of all the clinical scores study on a big number of patients is needed to draw from baseline evaluation to the 1, 3, 6, and 12 months definitive conclusions and enlarge the indications. Cattaneo et al. BMC Musculoskeletal Disorders (2018) 19:176 Page 7 of 7 Abbreviations 11. Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of ASCs: Adipose-derived stem cells; FC: Femoral condyle; HA: Hyaluronic acid; multipotent stem cells. Mol Biol Cell. 2002;13:4279–95. KOOS: Knee Injury and Osteoarthritis Outcome Score; MSCs: Mesenchymal 12. Gimble JM, Guilak F, Bunnell BA. Clinical and preclinical translation of cell- stem cells; NSAIDs: Nonsteroidal anti-inflammatory drugs; OA: Osteoarthritis; based therapies using adipose tissue-derived cells. Stem Cell Res Ther. 2010;1:1. PF: Patellofemoral; PRP: Platelet-rich plasma; SVF: Stromal vascular fraction; 13. Aronowitz JA, Lockhart RA, Hakakian CS. 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BMC Musculoskeletal DisordersSpringer Journals

Published: May 30, 2018

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