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The infrapatellar fat pad (IFP) has until recently been viewed as a densely vascular and innervated intracapsular/extrasynovial tissue with biomechanical roles in the anterior compartment of the knee. Over the last decade, secondary to the proposition that the IFP and synovium function as a single unit, its recognized tight molecular crosstalk with emerging roles in the pathophysiology of joint disease, and the characterization of immune-related resident cells with varying phenotypes (e.g., pro and anti-inflammatory macrophages), this structural complex has gained increasing attention as a potential therapeutic target in patients with various knee pathologies including osteoarthritis (KOA). Furthermore, the description of the presence of mesenchymal stem/stromal cells (MSC) as perivascular cells within the IFP (IFP-MSC), exhibiting immunomodulatory, anti-fibrotic and neutralizing activities over key local mediators, has promoted the IFP as an alternative source of MSC for cell-based therapy protocols. These complementary concepts have supported the growing notion of immune and inflammatory events participating in the pathogenesis of KOA, with the IFP/synovium complex engaging not only in amplifying local pathological responses, but also as a reservoir of potential therapeutic cell-based products. Consequently, the aim of this review is to outline the latest discoveries related with the IFP/synovium complex as both an active participant during KOA initiation and progression thus emerging as a potential target, and a source of therapeutic IFP-MSCs. Finally, we discuss how these notions may help the design of novel treatments for KOA through modulation of local cellular and molecular cascades that ultimately lead to joint destruction.

Adult stem cells have unique properties in both proliferation and differentiation preference. In this study, we hypothesized that adipose stem cells have a depot-dependent lineage preference. Four rabbits were used to provide donor-matched adipose stem cells from either subcutaneous adipose tissue (ScAT) or infrapatellar fat pad (IPFP). Proliferation and multi-lineage differentiation were evaluated in adipose stem cells from donor-matched ScAT and IPFP. RNA sequencing (RNA-seq) and proteomics were conducted to uncover potential molecular discrepancy in adipose stem cells and their corresponding matrix microenvironments. We found that stem cells from ScAT exhibited significantly higher proliferation and adipogenic capacity compared to those from donor-matched IPFP while stem cells from IPFP displayed significantly higher chondrogenic potential compared to those from donor-matched ScAT. Our findings are strongly endorsed by supportive data from transcriptome and proteomics analyses, indicating a site-dependent lineage preference of adipose stem cells.

Abstract Background While epidemiological studies have reported a potential role for hypercholesterolemia (HCE) in osteoarthritis (OA), the association between HCE and OA has yet to be clarified. Adipose tissue is a primary locus for cholesterol metabolism and the presence of HCE reportedly causes adipose dysfunction. The knee joint contains adipose tissue in the form of the infrapatellar fat pad (IPFP), which has been shown to contribute to the pathophysiology of OA in the knee via the secretion of inflammatory mediators. However, the effect of HCE on the expression of inflammatory mediators in the IPFP has not been elucidated. Methods IPFP and synovial tissues (ST) were extracted from 145 subjects with OA, diagnosed by radiography, during total knee arthroplasty. OA patients were divided into three groups according to their total cholesterol levels (Desirable, Borderline high and High) based on the National Cholesterol Education Program Adult Treatment Panel III (NCEPATP III). We examined the expression of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES1), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 using real-time polymerase chain reaction and compared results among the Desirable, Borderline high and High groups. Results The mRNA expression levels of TNF-α, IL-1β, and IL-6 in ST and the IPFP were not significantly different among the three groups. COX-2 mRNA expression in ST and IPFP was likewise not different among the three groups. While the mRNA expression level of mPGES1 in ST was also not significantly different, that of mPGES1 in the IPFP was significantly lower in the High group than in the Desirable and Borderline high groups. Conclusion mRNA levels of mPGES-1 are reduced in the IPFP of knee OA patients with HCE. Additional studies are need to clarify the effect of mPGES-1 down-regulation in OA pathology.

Abstract Background Despite the importance of inflammation during the pathogenesis of cranial cruciate ligament disease (CCLD) in dogs and despite the latest knowledge suggesting a significant role of adipose tissue in osteoarthritis, the infrapatellar fat pad (IFP) was up to now mostly disregarded in veterinary investigations. In the present study, the inflammatory activity of the IFP, the main adipose structure within the stifle joint, was thoroughly investigated to evaluate its potential impact in the pathogenesis of this common disease of our canine companions. Samples of IFP, subcutaneous adipose tissue (ScAT) of the thigh and synovial fluid in both diseased (n = 36) and healthy control (n = 23) dogs were tested for their immune cell composition but also for interleukins (IL-1β, IL-6, IL-8, IL-10), degradative enzymes (MMP-1, MMP-3, MMP-13, TIMP-2, iNOS) and adipokines (leptin and adiponectin). Characterization of the immune cell composition was ascertained by fluorescence activated cell sorting. Gene expression and protein release of the inflammatory markers was determined by real RT-qPCR and ELISA. Results IFPs of dogs with CCLD had a significantly increased immune cell count with T cells (CD3) as the most abundant immune cells. T cells and macrophages (CD14) were significantly increased compared to healthy controls or corresponding ScAT. In addition, IFPs of dogs with CCLD demonstrated a significant increase on gene as well as protein level of multiple inflammatory indicators (IL-1β, IL-6, MMP-1, MMP-13) compared to the other tissues. TNFα was only increased on gene expression. Adipokine analysis showed higher secretion of adiponectin and lower leptin secretion in IFP from dogs with CCLD than from controls. In the synovial fluid from dogs with CCLD concentrations of IL-1β, MMP-1, MMP-13 as well as leptin were significantly increased compared to the synovial fluid from healthy control dogs. Conclusions The present study indicates that the IFP is a potential contributory factor in the pathogenesis of CCLD, due to its inflammatory phenotype and the proximity within the stifle joint. To determine the extent of this possible inter-relationship, further studies need to be undertaken.

Background: Anterior knee pain (AKP) is a major complication that occurs after anterior cruciate ligament reconstruction (ACLR), even when hamstring tendon (HT) grafts are used. Damage to the infrapatellar fat pad (IPFP) during arthroscopy can cause AKP. The purpose of this study was to evaluate the influence of IPFP preservation on clinical outcomes, including AKP, in patients who underwent ACLR with HT autografts using the inside-out technique. Methods: Forty-two patients who underwent primary ACLR with HT autografts were prospectively assessed for 2 years after surgery. They were randomly selected to undergo treatment with as much intercondylar IPFP preservation as possible or with intercondylar IPFP resection to confirm the ACL origin on the femoral and tibial sides, especially the femoral footprint in deep flexion of the knee joint. The total IPFP volume was calculated using sagittal MR images before and 6 months after surgery. The patients completed a subjective knee score questionnaire and were assessed for patellar tendon tenderness and pain with the half-squat test or single-leg hop test at 6 months and 2 years postoperatively. Results: There were no differences in the patient characteristics, including age, sex, BMI, time from injury to surgery, and meniscus tear. The difference in the total size of the IPFP preserved was significant (P = 0.004). However, there were no significant differences in the subjective knee scores. Moreover, there were no differences in the clinical assessment parameters between the IPFP preservation and resection groups. Conclusions: The size of the IPFP decreased more in the resection group than in the preservation group at 6 months after surgery. However, partial IPFP resection, which was used to better visualize the origin of the ACL, had no effect on the clinical outcomes, including AKP. Level of evidence: Level II. [ABSTRACT FROM AUTHOR]

Mesenchymal stem/stromal cell (MSC)-based therapies have gained attention as potential alternatives for multiple musculoskeletal indications based on their trophic and immunomodulatory properties. The infrapatellar fat pad (IFP) serves as a reservoir of MSCs, which play crucial roles modulating inflammatory and fibrotic events at the IFP and its neighboring tissue, the synovium. In an effort to comply with the existing regulatory framework regarding cell-based product manufacturing, we interrogated the in vitro immunomodulatory capacity of human-derived IFP-MSCs processed under different conditions, including a regulatory-compliant protocol, in addition to their response to the inflammatory and fibrotic environments often present in joint disease. Immunophenotype, telomere length, transcriptional and secretory immunomodulatory profiles and functional immunopotency assay were assessed in IFP-MSCs expanded in regular fetal bovine serum (FBS)-supplemented medium and side-by-side compared with same-donor cells processed with two media alternatives (i.e., regulatory-compliant pooled human platelet lysate [hPL] and a chemically reinforced/serum-reduced [Ch-R] formulation). Finally, to assess the effects of such formulations on the ability of the cells to respond to pro-inflammatory and pro-fibrotic conditions, all three groups were stimulated ex vivo (i.e., cell priming) with a cocktail containing TNFα, IFNγ and connective tissue growth factor (tumor-initiating cells) and compared with non-induced cohorts assessing the same outcomes. Non-induced and primed IFP-MSCs expanded in either hPL or Ch-R showed distinct morphology in vitro , similar telomere dynamics and distinct phenotypical and molecular profiles when compared with cohorts grown in FBS. Gene expression of IL-8, CD10 and granulocyte colony-stimulating factor was highly enriched in similarly processed IFP-MSCs. Cell surface markers related to the immunomodulatory capacity, including CD146 and CD10, were highly expressed, and secretion of immunomodulatory and pro-angiogenic factors was significantly enhanced with both hPL and Ch-R formulations. Upon priming, the immunomodulatory phenotype was enhanced, resulting in further increase in CD146 and CD10, significant CXCR4 presence and reduction in TLR3. Similarly, transcriptional and secretory profiles were enriched and more pronounced in IFP-MSCs expanded in either hPL or Ch-R, suggesting a synergistic effect between these formulations and inflammatory/fibrotic priming conditions. Collectively, increased indoleamine-2,3-dioxygenase activity and prostaglandin E2 secretion for hPL- and Ch-R-expanded IFP-MSCs were functionally reflected by their robust T-cell proliferation suppression capacity in vitro compared with IFP-MSCs expanded in FBS, even after priming. Compared with processing using an FBS-supplemented medium, processing IFP-MSCs with either hPL or Ch-R similarly enhances their immunomodulatory properties, which are further increased after exposure to an inflammatory/fibrotic priming environment. This evidence supports the adoption of regulatory-compliant practices during the manufacturing of a cell-based product based on IFP-MSCs and anticipates a further enhanced response once the cells face the pathological environment after intra-articular administration. Mechanistically, the resulting functionally enhanced cell-based product has potential utilization as a novel, minimally invasive cell therapy for joint disease through modulation of local immune and inflammatory events. [ABSTRACT FROM AUTHOR]

Osteoarthritis is the most common joint disease, commonly affecting the knee, and total knee arthroplasties have greatly increased in recent decades. The infrapatellar fat pad, also known as Hoffa's fat pad, is often resected during total knee arthroplasty in order to improve the surgeon's visibility/access. In the relevant literature there is no consensus regarding infrapatellar fat pad preservation. Its resection may affect the blood supply to the patellar tendon, and it may also be blamed for other postoperative changes in the knee. On the other hand, preservation of the fat pad has been associated with increased postoperative anterior knee pain. It is preferable that the surgeon should try to preserve the infrapatellar fat pad, but if preservation causes problems regarding visibility and access, it should be removed. The choice of full resection, preservation or partial resection of the fat pad depends on the surgeon's preferences and experience, and on the needs of the patient. [ABSTRACT FROM AUTHOR]

Osteoarthritis is the most prevalent arthritis typically characterized by degradation of cartilage. However, its pathogenesis is not fully understood. Currently, osteoarthritis is best considered a disease of the whole "joint organ". Infrapatellar fat pad (IFP), an adipose tissue near synovium, is now attaching importance to researchers for its inflammatory phenotype. In this narrative review, a large body of evidence has been gathered for the involvement of IFP in the development of knee osteoarthritis. Additionally, the underlying mechanisms of how IFP can be involved in this process have been proposed. However, further investigations are needed to better understand its precise role in this process and its underlying mechanism, and beyond that, to develop new strategies to slow down the degenerative process and explore an effective and timely diagnosis of the disease. [ABSTRACT FROM AUTHOR]

The infrapatellar fat pad is an adipose tissue in the knee that facilitates the distribution of synovial fluid and absorbs impulsive actions generated through the joint. The correlation between morphological configuration and mechanical properties is analyzed by a computational approach. The microscopic anatomy of the infrapatellar fat pad is studied aiming to measure the dimension of adipose lobules and the thickness of connective septa. Results from histomorphometric investigations show that the infrapatellar fat pad is an inhomogeneous tissue, constituted by large lobules in the superficial part and smaller lobules in the deepest one. Finite element models of the infrapatellar fat pad are developed. The first model considers the inhomogeneous conformation of the infrapatellar fat pad, composed of micro- and macro-chambers, while the second model considers a homogeneous distribution of adipose lobules with similar dimensions. Computational analyses are performed considering the static standing configuration and the passive flexion-extension movement. The computational results allow us to identify the different stress and strain fields within the tissue and to appreciate the variation of the mechanical performance of the overall system considering the distribution of adipose lobules. Results show that the distribution of adipose lobules in macro- and micro-chambers allows major deformation of the infrapatellar fat pad, decreasing the stress inside the tissues. [ABSTRACT FROM AUTHOR]

Copyright of Rigakuryoho Kagaku is the property of International Press Editing Center Incorporation and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Adipose tissue is a rich source of stem cells, which are reported to represent 2% of the stromal vascular fraction (SVF). The infrapatellar fat pad (IFP) is a unique source of tissue, from which human adipose-derived stem cells (hADSCs) have been shown to harbour high chondrogenic potential. This review aims to calculate, based on the literature, the culture time needed before an average knee articular cartilage defect can be treated using stem cells obtained from arthroscopically or openly harvested IFP. Firstly, a systematic literature review was performed to search for studies that included the number of stem cells isolated from the IFP. Subsequent analysis was conducted to identify the amount of IFP tissue harvestable, stem cell count and the overall yield based on the harvesting method. We then determined the minimum time required before treating an average-sized knee articular cartilage defect with IFP-derived hADSCs by using our newly devised equation. The amount of fat tissue, the SVF cell count and the stem cell yield are all lower in arthroscopically harvested IFP tissue compared to that collected using arthrotomy. As an extrapolation, we show that an average knee defect can be treated in 20 or 17 days using arthroscopically or openly harvested IFP-derived hADSCs, respectively. In summary, the systematic review conducted in this study reveals that there is a higher amount of fat tissue, SVF cell count and overall yield (cells/volume or cells/gram) associated with open (arthrotomy) compared to arthroscopic IFP harvest. In addition to these review findings, we demonstrate that our novel framework can give an indication about the culture time needed to scale up IFP-derived stem cells for the treatment of articular cartilage defects based on harvesting method. [ABSTRACT FROM AUTHOR]

Background: The infrapatellar fat pad (IPFP) or Hoffa's fat pad is often resected during total knee arthroplasty in order to improve visibility. However, the management of the IPFP during total knee arthroplasty (TKA) is the subject of an ongoing debate that has no clear consensus. The purpose of this review was to appraise if resection of the IPFP affects clinical outcomes. Methods: We conducted a meta-analysis to identify relevant randomized controlled trials involving infrapatellar fat pad resection and infrapatellar fat pad preservation during total knee arthroplasty in electronic databases, including Web of Science, Embase, PubMed, Cochrane Controlled Trials Register, Cochrane Library, Highwire, CBM, CNKI, VIP, and Wanfang database, up to March 2020. Results: Nine randomized controlled trials, involving 783 TKAs (722 patients), were included in the systematic review. Outcome measures included patellar tendon length (PTL), Insall-Salvati ratio (ISR), rate of anterior knee pain, Knee Society Scores (KSS), and knee range of motion. The meta-analysis identified a trend toward the shortening of the patellar tendon with IPFP resection at 6 months (P = 0.0001) and 1 year (P = 0.001). We found no statistical difference in ISR (P = 0.87), rate of anterior knee pain within 6 months (p = 0.45) and 1 year (p = 0.38), KSS at 1 year (p = 0.77), and knee range of motion within 6 months (p = 0.61) and 1 year (0.46). Conclusion: Based on the available level I evidence, we were unable to conclude that one surgical technique of IPFP can definitively be considered superior over the other. More adequately powered and better-designed randomized controlled trial (RCT) studies with long-term follow-up are required to produce evidence-based guidelines regarding IPFP resection. [ABSTRACT FROM AUTHOR]

Purpose: A central patellar (CP) portal can be used to view the native femoral insertion site of the anterior cruciate ligament (ACL). It aids in the drilling of an anatomical tunnel; however, its impact on the patellar tendon and the infrapatellar fat pad remains a concern. The aim of this study was to investigate complications associated with the CP portal use in arthroscopic ACL reconstruction (ACLR).Methods: A total of 105 patients (107 knees, 60 females) who underwent ACLR with a CP portal from 2012 to 2017 were included in this study. The mean age was 28.3 ± 12.4 years. All surgeries were single-bundle reconstructions using the trans-tibial technique via the CP and anteromedial portals. Post-operative events, magnetic resonance imaging (MRI), and arthroscopic findings associated with CP portal creation were evaluated.Results: Five patients (4.7%) had symptomatic postoperative complications, which included two patients with patellar tendonitis and three patients with fibrosis in the anterior knee compartment. Abnormal signal intensity of the patellar tendon on MRI and increased thickness at the CP portal area were found in 18 of 25 knees (72%). Three of 56 knees (5.4%) that underwent second-look arthroscopy showed fibrosis of the infrapatellar fat pad. Seven patients (12.5%) showed hypertrophy of the ligamentum mucosum.Conclusions: The rate of symptomatic complications associated with CP portal placement was 4.7%; however, abnormal MRI or follow-up arthroscopy findings were much higher than clinically symptomatic patients. This study suggests that CP portal placement could provoke anterior knee compartment fibrosis or hypertrophy.Level Of Evidence: IV. [ABSTRACT FROM AUTHOR]

The infrapatellar fat pad (IFP) is an extrasynovial, intracapsular, adipose body occupying the space in the knee joint between the inferior border of the patella, the femoral condyles, tibial plateau and patellar tendon. Little is known about the anatomy and normal function of the IFP, but it has been suggested to play a role in the aetiology of Anterior knee pain syndrome, including that associated with osteoarthritis. Forty‐three knees from 11 male and 15 female embalmed cadavers (mean age 84 years; range 55–97 years) were investigated. The cadavers were donated and the study performed in compliance with the provisions of the UK Human Tissue Act (2004). The quadriceps tendon and the medial and lateral patellar retinacula were dissected from the patella, which was then reflected antero‐distally. The IFP was carefully excised and details of its morphology and attachments to components of the knee joint were recorded, together with the presence of articular surface pathology on the patella and femoral condyles. The principal novel findings of the current study were that 81% of IFPs were attached to the superior border of the patella by supero‐medial extensions and 65% were attached by supero‐lateral extensions; the supero‐medial extensions were larger than the supero‐lateral extensions. The superior extensions of the IFP were always attached anteriorly to the patellar retinacula and in four individuals the extensions formed a full loop around the superior border of the patella. The volume of IFPs with attachments to the superior border of the patella was significantly greater (p =.007) than those without, and the IFP was attached to the medial meniscus in significantly (p =.009) more knees with IFP attachment to the superior border of the patella than those without. All IFPs were attached to the medial anterior horn of the meniscus and the medial Kaplan's ligament. Ninety‐seven per cent were attached to the lateral anterior horn of the meniscus and 97% to the lateral Kaplan's ligament. The length of IFP attachment to the lateral meniscus was significantly longer (p =.004) than that to the medial meniscus. Ninety‐seven per cent of IFPs were attached to the superior portion of the patellar tendon with the mean tendon attachment being 60%. Ninety‐one per cent of IFPs were attached to the inferior border of the patella. Significantly fewer knees with patellar (p =.001) and femoral (p =.002) articular surface osteophytes exhibited superior IFP extensions and these extensions were significantly shorter in knees with patellar (p =.000) and femoral (p =.006) osteophytes, compared with those without. The IFP was attached to the medial meniscus in significantly fewer knees with femoral (p =.050) and patellar (p =.023) osteophytes than those without. All IFPs not attached to the anterior horn of the lateral menisci, medial Kaplan's ligament, superior patella or inferior border of the patella, were in knees with articular surface osteophytes. This relationship between IFP morphology and knee joint pathology suggests a functional role for the IFP that requires further investigation. [ABSTRACT FROM AUTHOR]

The infrapatellar fat pad (IFP) contains nerve fiber endings and is considered to play an important role in the perception of knee pain. However, it is unclear whether and to what degree prolonged pain influences the nociceptive role of the IFP. To answer this question, we established a novel rat model of knee pain in which inflammation is restricted to the IFP. Rats received a single intra‐IFP injection of monoiodoacetic acid (MIA) (0.2 mg/10 µL or 1.0 mg/10 µL) in the left knee and a phosphate‐buffered saline (10 µL) injection in the right knee as a control. Pain‐avoidance behavior and histological changes of the knee joint were measured at multiple time points up to 28 days after MIA injection. Histological analysis showed a transient inflammatory response in the IFP body in the 0.2‐mg model, whereas prolonged inflammation followed by fibrotic changes was observed in the 1.0‐mg model. Subtle histological alterations were observed in the articular cartilage and IFP surface regardless of the dose. The pain‐avoidance behavior test indicated the development of prolonged knee pain throughout the experimental period in the 1.0‐mg group. Histological assessments showed a significant increase in calcitonin gene‐related peptide (CGRP)‐positive nerve fiber endings inside IFPs with fibrosis in newly vascularized surrounding regions. These data suggest that irreversible fibrotic changes in the IFP induce the formation of new vessels and CGRP‐positive nerve fiber endings that associate prolonged pain in the joint. [ABSTRACT FROM AUTHOR]

Copyright of Rigakuryoho Kagaku is the property of International Press Editing Center Incorporation and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Osteoarthritis (OA) is a family of degenerative diseases affecting multiple joint tissues. Despite the diverse etiology and pathogenesis of OA, increasing evidence suggests that macrophages can play a significant role in modulating joint inflammation, and thus OA severity, via various secreted mediators. Recent advances in next-generation sequencing technologies coupled with proteomic and epigenetic tools have greatly facilitated research to elucidate the embryonic origin of macrophages in various tissues including joint synovium. Furthermore, scientists have now begun to appreciate that macrophage polarization can span beyond the conventionally recognized binary states (i.e., pro-inflammatory M1-like vs anti-inflammatory M2-like) and may encompass a broad spectrum of phenotypes. Although the presence of these cells has been shown in multiple joint tissues, additional mechanistic studies are required to provide a comprehensive understanding of the precise role of these diverse macrophage populations in OA onset and progression. New approaches that can modulate macrophages into desired functional phenotypes may provide novel therapeutic strategies for preventing OA or enhancing cartilage repair and regeneration. [ABSTRACT FROM AUTHOR]

Background: The infiltration of the stromal vascular fraction (SVF) of autologous adipose tissue to treat osteoarthritis has been used for several years demonstrating its safety and noticeable efficacy. This article presents clinical data from patients afftected by moderate and severe knee osteoarthritis demonstrating safety and clinical efficacy of the treatment when this autologous cell product is injected in the knee joint and patients evaluated post-operatively after 1 year. However, what do we know about the mechanism that underlies this clinical improvement? This article proposes, for the first time in our opinion, a hypothesis of the mode of action that involves structural and molecular interactions between SVF and infrapatellar fat pad (IFP). As consequence, there would be a re-education of intra-articular adipose tissue, which we consider a key player for the clinical effect observed in the mid and long term mainly due to immuno-regulatory mechanisms. Methods: This is a retrospective and not controlled study that evaluated 50 patients (100 joints) ranging from 50 to 89 years old, separated by age cohorts. Clinical efficacy was assessed using the Lequesne, WOMAC, and VAS scales, by ultrasound control and quantification of the biochemical profiles of synovial fluid. Results: There were no serious adverse effects. All the indexes studied showed a significant clinical improvement after 1-year follow-up for all ages and OA degree groups. This finding was correlated with the ultrasound observations and biochemical data, which show a marked decrease in catabolic and pro-inflammatory molecules (MMP-2, IL-1B, IL-6, and IL-8) and significant increase for anabolic and anti-inflammatory molecules (IGF-1 and IL-10). Conclusions: We conclude that intra-articular SVF infiltration for knee OA treatment is safe and effective during 1 year. We propose that applied SVF cells cause a cascade of molecular and structural events that, through complex interactions between IFP and SVF, re-educating the intra-articular fatty tissue towards a homeostatic, protective, and anti-inflammatory function, which will ultimately promote the restructuring and regeneration of damaged tissues. [ABSTRACT FROM AUTHOR]

Knee osteoarthritis (OA) involves several structures and molecules in the joint, which interact in a pathophysiological process. One of these molecules is the cartilage oligomeric matrix protein (COMP). Elevated COMP levels in the synovial fluid as well as in the serum have been described in OA patients. However, this has not been described in the infrapatellar fat pad (IPFP) tissue before. In this prospective trial, we collected 14 IPFPs from patients with high‐grade OA (mean age 63.8 ± 17.6 years) who underwent total knee replacement (OA group) and from 11 healthy patients (mean age 33.7 ± 14.8 years) who underwent anterior cruciate ligament reconstruction (control group). The presence of macrophages (CD68 and CD206) and proinflammatory cytokines (interleukin 1β [IL‐1β] and IL‐6) was analyzed. Histological and immunohistological examinations as well as immunoblotting analysis for COMP, leptin, and matrix‐metalloproteinase‐3 were performed. The IPFPs of both the OA and control group consisted of adipose tissue and fibrous tissue, and the fibrous tissue showed higher score values than the adipose tissue for COMP staining (intensity as well as stained area) in both groups. Although COMP could be detected in most samples, leptin expression was found only in single specimens. COMP could be detected mostly in the fibrous tissue portion of the IPFP. We speculate that it is involved in a remodeling process taking place in the IPFP during OA. Presence of leptin was irregular in immunohistology, and the control group showed higher scores in case of presence. Interestingly, immunoblotting could detect leptin in all analyzed samples. © 2019 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society J Orthop Res 38:747‐758, 2020 [ABSTRACT FROM AUTHOR]

• Three cases of para-articular osteochondroma, a rare benign disease, are presented. • Symptoms at presentation included chronic knee pain and limited knee movement. • Simple marginal resection using an open approach was performed. • Post-surgery, the pain disappeared and the range of motion of the knee was restored. Para-articular osteochondromas are not very common. We performed simple marginal excision for three cases. We encountered three cases of para-articular osteochondroma of the infrapatellar fat pad. All patients were men, with an average age of 43 years. The symptoms were very similar to those of anterior knee pain, which were increasing swelling and reduction of the range of motion. After simple marginal excision was performed, the symptoms improved and no recurrences or malignant transformation occurred during the mean postoperative period of 51 months. Forty-seven cases of para-articular osteochondroma have been reported, and excision is the standard treatment. Local recurrence has been reported in only one case, and malignant transformation has never been reported. However, in some reports there was no specification of the excision method, which was simply referred to as "excision." Thus, we used a simple marginal excision for all three of our cases. We report three cases of para-articular osteochondroma of the infrapatellar fat pad that were effectively treated using simple marginal excision. [ABSTRACT FROM AUTHOR]

Cartilage defects are a predisposing factor for osteoarthritis. Conventional therapies are mostly palliative and there is an interest in developing newer therapies that target the disease’s progression. Mesenchymal stem cells (MSCs) have been suggested as a promising therapy to restore hyaline cartilage to cartilage defects, though the optimal cell source has remained under investigation. A PRISMA systematic review was conducted utilising five databases (MEDLINE, EMBASE, Cochrane Library, Scopus, Web of Science) which identified nineteen human studies that used adipose tissue-derived MSC (AMSC)-based therapies, including culture-expanded AMSCs and stromal vascular fraction, to treat cartilage defects. Clinical, imaging and histological outcomes, as well as other relevant details pertaining to cartilage regeneration, were extracted from each study. Pooled analysis revealed a significant improvement in WOMAC scores (mean difference: −25.52; 95%CI (−30.93, −20.10); p < 0.001), VAS scores (mean difference: −3.30; 95%CI (−3.72, −2.89); p < 0.001), KOOS scores and end point MOCART score (mean: 68.12; 95%CI (62.18, 74.05)), thus showing improvement. The studies in this review demonstrate the safety and efficacy of AMSC-based therapies for cartilage defects. Establishing standardised methods for MSC extraction and delivery, and performing studies with long follow-up should enable future high-quality research to provide the evidence needed to bring AMSC-based therapies into the market.

The pathogenesis and progression of knee inflammatory pathologies is modulated partly by residing macrophages in the infrapatellar fat pad (IFP), thus, macrophage polarization towards pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes is important in joint disease pathologies. Alteration of M1/M2 balance contributes to the initiation and progression of joint inflammation and can be potentially altered with mesenchymal stem cell (MSC) therapy. In an acute synovial/IFP inflammation rat model a single intra-articular injection of IFP-MSC was performed, having as controls (1) diseased rats not receiving IFP-MSC and (2) non-diseased rats. After 4 days, cell specific transcriptional profiling via single-cell RNA-sequencing was performed on isolated IFP tissue from each group. Eight transcriptomically distinct cell populations were identified within the IFP across all three treatment groups with a noted difference in the proportion of myeloid cells across the groups. Largely myeloid cells consisted of macrophages (>90%); one M1 sub-cluster highly expressing pro-inflammatory markers and two M2 sub-clusters with one of them expressing higher levels of canonical M2 markers. Notably, the diseased samples (11.9%) had the lowest proportion of cells expressing M2 markers relative to healthy (14.8%) and MSC treated (19.4%) samples. These results suggest a phenotypic polarization of IFP macrophages towards the pro-inflammatory M1 phenotype in an acute model of inflammation, which are alleviated by IFP-MSC therapy inducing a switch towards an alternate M2 status. Understanding the IFP cellular heterogeneity and associated transcriptional programs may offer insights into novel therapeutic strategies for disabling joint disease pathologies.

Abstract Background Obesity is associated with the development and progression of osteoarthritis (OA). Although the infrapatellar fat pad (IFP) could be involved in this association, due to its intracapsular localization in the knee joint, there is currently little known about the effect of obesity on the IFP. Therefore, we investigated cellular and molecular body mass index (BMI)-related features in the IFP of OA patients. Methods Patients with knee OA (N = 155, 68% women, mean age 65 years, mean (SD) BMI 29.9 kg/m2 (5.7)) were recruited: IFP volume was determined by magnetic resonance imaging in 79 patients with knee OA, while IFPs and subcutaneous adipose tissue (SCAT) were obtained from 106 patients undergoing arthroplasty. Crown-like structures (CLS) were determined using immunohistochemical analysis. Adipocyte size was determined by light microscopy and histological analysis. Stromal vascular fraction (SVF) cells were characterized by flow cytometry. Results IFP volume (mean (SD) 23.6 (5.4) mm3) was associated with height, but not with BMI or other obesity-related features. Likewise, volume and size of IFP adipocytes (mean 271 pl, mean 1933 μm) was not correlated with BMI. Few CLS were observed in the IFP, with no differences between overweight/obese and lean individuals. Moreover, high BMI was not associated with higher SVF immune cell numbers in the IFP, nor with changes in their phenotype. No BMI-associated molecular differences were observed, besides an increase in TNFα expression with high BMI. Macrophages in the IFP were mostly pro-inflammatory, producing IL-6 and TNFα, but little IL-10. Interestingly, however, CD206 and CD163 were associated with an anti-inflammatory phenotype, were the most abundantly expressed surface markers on macrophages (81% and 41%, respectively) and CD163+ macrophages had a more activated and pro-inflammatory phenotype than their CD163- counterparts. Conclusions BMI-related features usually observed in SCAT and visceral adipose tissue could not be detected in the IFP of OA patients, a fat depot implicated in OA pathogenesis.

Abstract Background The infrapatellar fat pad (IPFP) has been implicated as a possible source of osteoarthritis (OA) development and knee pain due to the production of inflammatory mediators and the existence of nerve fibers within this structure. Calcitonin gene-related peptide (CGRP) is a vasodilatory neuropeptide that is localized to joint tissues and has recently been implicated in the development of knee OA and OA pain. To date, however, the expression levels of CGRP in the IPFP of human knee OA patients have not been examined. Methods IFFP and synovial (SYN) tissues were harvested from 100 individuals with radiographic knee OA (unilateral Kellgren/Lawrence [K/L] grades 2–4) during total knee arthroplasty and subjected to immunohistochemical analysis for CGRP localization. In addition, the messenger RNA (mRNA) expression levels of CGRP and cyclooxygenase-2 (COX-2) in the collected tissues were evaluated and compared using real-time PCR analysis of total RNA extracts. CGRP and COX-2 mRNA expression were also compared among individuals with K/L grades 2–4. Results CGRP-positive cells were detected in the capillaries within the IPFP and lining layer of SYN tissue. The expression levels of CGRP in the IPFP were positively correlated with COX-2 and were significantly higher than those in SYN tissue. CGRP expression in tissue from the KL4 group was twofold higher than that from the KL2 group. Conclusions The IPFP of knee OA patients produces relatively high levels of CGRP, which may be regulated by COX-2 at the transcriptional level. Further studies are needed to determine if CGRP levels are directly linked to OA pathology.

Recently, infrapatellar fat pad (IFP) has been considered as a source of stem cells for cartilage regeneration in osteoarthritis (OA) due to their ability for differentiation into chondrocytes. However, stressful conditions, like that related to OA, may induce a pathogenic reprograming. The aim of this study was to characterize the structural and functional properties of a new population of stem cells isolated from osteoarthritic infrapatellar fat pad (OA-IFP). Nine OA patients undergoing total knee arthroplasty (TKA) were enrolled in this study [median age = 74 years, interquartile range (IQR) = 78.25-67.7; median body mass index = 29.4 Kg/m2, IQR = 31.7-27.4]. OA-IFP stem cells were isolated and characterized for morphology, stemness, metabolic profile and multi-differentiative potential by transmission electron microscopy, flow cytometric analysis, gene expression study and cytochemistry. OA-IFP stem cells displayed a spindle-like morphology, self-renewal potential and responsiveness (CD44, CD105, VEGFR2, FGFR2, IL1R, and IL6R) to microenvironmental stimuli. Characterized by high grade of stemness (STAT3, NOTCH1, c-Myc, OCT-4, KLF4, and NANOG), the cells showed peculiar immunophenotypic properties (CD73+/CD39+/CD90+/CD105+/CD44–/+/CD45–). The expression of HLA-DR, CD34, Fas and FasL was indicative of a possible phenotypic reprograming induced by inflammation. Moreover, the response to mechanical stimuli together with high expression level of COL1A1 gene, suggested their possible protective response against in vivo mechanical overloading. Conversely, the low expression of CD38/NADase was indicative of their inability to counteract NAD+-mediated OA inflammation. Based on the ultrastructural, immunophenotypic and functional characterization, OA-IFP stem cells were hypothesized to be primed by the pathological environment and to exert incomplete protective activity from OA inflammation.

Summary: Objectives: To clarify the effects of mechanical unloading on joint components, including the articular cartilage by knee compartments, synovial membrane, and the infrapatellar fat pad (IFP), using a hindlimb suspension rat model. Design: Twenty-five male rats were divided into the three following experimental groups: the baseline, control (CON), and hindlimb unloading (HU) groups. Rats in the HU group were subjected to periods of hindlimb unloading by tail suspension. The joint components were evaluated by histopathological and histomorphometric analyses. Results: The unloading condition caused articular cartilage thinning and decreased matrix staining. The tendency of these histological changes in articular cartilage was similar between the knee compartments. In general, the unloading environment resulted in no critical histological changes to the synovial membrane and IFP. At 4 weeks, thickening of the synovial membrane and synovial-like tissue invasion were observed in the HU group, but there was no significant change in inflammation. There was no obvious histological change to the IFP caused by unloading. Conclusion: The unloading environment caused disuse histological changes in the articular cartilage; however, the tendency of the changes was similar between compartments. Furthermore, the unloading condition caused no critical histological changes to the synovial membrane or IFP. Clinically, the unloading environment without joint immobilization over a short period may not have caused critical histological changes to the joint components.

Osteoarthritis is a prevalent, complex disease of the joints, and affects multiple intra-articular tissues. Here, we have examined genome-wide DNA methylation profiles of primary infrapatellar fat pad and matched blood samples from 70 osteoarthritis patients undergoing total knee replacement surgery. Comparing the DNA methylation profiles between these tissues reveal widespread epigenetic differences. We produce the first genome-wide methylation quantitative trait locus (mQTL) map of fat pad, and make the resource available to the wider community. Using two-sample Mendelian randomization and colocalization analyses, we resolve osteoarthritis GWAS signals and provide insights into the molecular mechanisms underpinning disease aetiopathology. Our findings provide the first view of the epigenetic landscape of infrapatellar fat pad primary tissue in osteoarthritis., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: In knee osteoarthritis (OA), macrophages are the most predominant immune cells that infiltrate synovial tissues and infrapatellar fat pads (IPFPs). Both M1 and M2 macrophages have been described, but their role in OA has not been fully investigated. Therefore, we investigated macrophage subpopulations in IPFPs and synovial tissues of knee OA patients and their correlation with disease severity, examined their transcriptomics, and tested for factors that influenced their polarization., Methods: Synovial tissues and IPFPs were obtained from knee OA patients undergoing total knee arthroplasty. Macrophages isolated from these joint tissues were characterized via flow cytometry. Transcriptomic profiling of each macrophage subpopulations was performed using NanoString technology. Peripheral blood monocyte-derived macrophages (MDMs) were treated with synovial fluid and synovial tissue- and IPFP-conditioned media. Synovial fluid-treated MDMs were treated with platelet-rich plasma (PRP) and its effects on macrophage polarization were observed., Results: Our findings show that CD11c+CD206+ macrophages were predominant in IPFPs and synovial tissues compared to other macrophage subpopulations (CD11c+CD206-, CD11c-CD206+, and CD11c-CD206- macrophages) of knee OA patients. The abundance of macrophages in IPFPs reflected those in synovial tissues but did not correlate with disease severity as determined from Mankin scoring of cartilage destruction. Our transcriptomics data demonstrated highly expressed genes that were related to OA pathogenesis in CD11c+CD206+ macrophages than CD11c+CD206-, CD11c-CD206+, and CD11c-CD206- macrophages. In addition, MDMs treated with synovial fluid, synovial tissue-conditioned media, or IPFP-conditioned media resulted in different polarization profiles of MDMs. IPFP-conditioned media induced increases in CD86+CD206+ MDMs, whereas synovial tissue-conditioned media induced increases in CD86+CD206- MDMs. Synovial fluid treatment (at 1:8 dilution) induced a very subtle polarization in each macrophage subpopulation. PRP was able to shift macrophage subpopulations and partially reverse the profiles of synovial fluid-treated MDMs., Conclusion: Our study provides an insight on the phenotypes and genotypes of macrophages found in IPFPs and synovial tissues of knee OA patients. We also show that the microenvironment plays a role in driving macrophages to polarize differently and shifting macrophage profiles can be reversed by PRP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hengtrakool, Leearamwat, Sengprasert, Wongphoom, Chaichana, Taweevisit, Ngarmukos, Tanavalee, Palaga and Reantragoon.)

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Background: Mesenchymal stromal cell (MSC)–based therapies have emerged as a promising strategy for osteoarthritis (OA) treatment. In particular, infrapatellar fat pad (IPFP)–derived MSCs have become a good option to treat knee OA. Purpose: To investigate the influence of the local microenvironment of the knee joint, especially OA cartilage, on the bioactivities of injected/implanted IPFP MSCs. Study Design: Controlled laboratory study. Methods: Conditioned medium (CM) derived from OA cartilage fragments was collected and characterized. Donor-matched IPFP MSCs were treated with control medium (Dulbecco's modified Eagle medium (DMEM)/F-12 or chondrogenic medium), control medium + CM, or CM alone; and a series of behaviors including the viability, migration, chondrogenic and hypertrophic differentiation, and catabolic activity of IPFP MSCs were evaluated among groups. Results: There were 14 cytokines detected in CM. CM treatment improved the viability of IPFP MSCs. CM hindered the migration of IPFP MSCs. In chondrogenic differentiation, the presence of CM increased the expression of chondrogenic markers but also enhanced the state of hypertrophy and catabolism. Conclusion: OA cartilage–secreted factors could induce chondrogenic differentiation but also resulted in negative effects including the weakened migration, increased hypertrophy, and catabolism of IPFP MSCs in vitro. Clinical Relevance: These findings provide an insight on the fate of IPFP MSCs after intra-articular injections. [ABSTRACT FROM AUTHOR]

The infrapatellar fat pad (IPFP) is a periarticular adipose knee tissue. This tissue contains a large number of mesenchymal stem cells (MSCs). In the present work, we wanted to study the IPFP MSCs and their relationship and differences in two groups, anterior cruciate ligament (ACL) ruptures knees and ostheoarthrosis (OA). The IPFP of 42 patients with OA or ACL rupture were analyzed. Isolation, primary culture, and a genetic and proteomic study of MSCs from IPFP were performed. Gene expression of IL‐6, tumor necrosis factor (TNF), IL‐8, HSPA1A (Hsp70), CXCL10, RANTES, MMP1, MMP3, TIMP1, and BMP7 was analyzed by real‐time quantitative polymerase chain reaction (RT‐qPCR). We analyzed MSCs from from 12 diferents patients in two cellular pools (6 from AO disease and 6 from ALC rupture to form two cell pool), for the iTRAQ Proteomic Assay. The conditional media were used in quantitative analysis of MSC soluble factors by Luminex and for de migration assay. A higher gene expression of IL‐6, TNF, CXCL10, RANTES, and MMP1 and OPG in MSCs from OA versus ACL (p < 0.05) was observed. Conversely HSPA1A, TIMP1, and RANKL showed a significant lower expression in OA‐MSCs (p < 0.05). In the secretome analysis, adipsin and visfantin levels in the supernatants from OA‐MSCs were lower (p < 0.05) respect to ACL‐MSCs. Also, the monocytic cells migrated two‐folds in the presence of conditioned media from OA‐MSCs patients versus patients with ACL‐MSC. The infrapatellar pad should be considered as an adipose tissue capable of producing and excreting inflammatory mediators directly in the knee joint, influencing the development and progression of knee joint pathologies. [ABSTRACT FROM AUTHOR]

Infrapatellar fat pad-derived stem cells (IFPSCs) are emerging as an alternative to adipose tissue-derived stem cells (ADSCs) from other sources. They are a reliable source of autologous stem cells obtained from medical waste that are suitable for use in cell-based therapy, tissue engineering and regenerative medicine. Such clinical applications require a vast number of high-quality IFPSCs. Unlike embryonic stem cells (ESCs), ADSCs and IFPSCs have limited population doubling capacity; however, in vitro expansion of primary IFPSCs through multiple passages (referred to as P) is a crucial step to acquire the desired population of cells. The present study investigated the effect of multiple passages on the stemness of IFPSCs during expansion and the possibility of predicting the loss of stemness using certain markers. IFPSCs were isolated from infrapatellar fat pad tissue resected during knee arthroplasty performed on aged patients (>65 years old). These cells from the stromal vascular fraction were serially passaged to at least to P7, and their stemness characteristics were examined at each passage. It was observed that IFPSCs maintained their spindle-shaped morphology, self-renewability and homogeneity at P2-4. Furthermore, immunostaining revealed that these cells expressed mesenchymal stem cell (CD166, CD90 and CD105) and ESC markers [Sox2, Nanog, Oct4 and nucleostemin (NS)], whereas the hematopoietic stem cell marker CD45 was absent. These cells were also able to differentiate into the three germ layer cell types, thus confirming their ability to generate clinical grade cells. The findings indicated that prolonged culture of IFPSCs (P>6) led to the loss of the stem cell proliferative marker NS, with an increased population doubling time and progression toward neuronal differentiation, acquiring a neurogenic phenotype. Additionally, IFPSCs demonstrated an inherent ability to secrete neurotrophic factors and express receptors for these factors, which is the cause of neuronal differentiation at later passages. Therefore, these findings validated NS as a prognostic indicator for impaired stemness and identified IFPSCs as a promising source for cell-based therapy, particularly for neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The infrapatellar fat pad (IFP) is an intracapsular but extrasynovial structure, located between the patellar tendon, the femoral condyles and the tibial plateau. It consists of white adipose tissue, organised in lobules defined by thin connective septa. The aim of this study is the morphometric and ultrasonographic analysis of IFP in subjects without knee pathology during flexion‐extension movements. The morphometric study was conducted on 20 cadavers (15M, 5F, mean age 80.2 years). Ultrasound was performed on 24 volunteers with no history of knee diseases (5M, 19F, mean age: 45 years). The characteristics of the adipose lobules near the patellar tendon and in the deep portion of the IFP were evaluated. Numerical models were provided, according to the size of the lobules. At histological examination, the adipose lobules located near the patellar tendon were larger (mean area 12.2 mm2 ± 5.3) than those at a deeper level (mean area 1.34 mm2 ± 0.7, P < 0.001) and the thickness of the septa of the deepest adipose lobules (mean value 0.35 mm ± 0.32) was greater than that of the superficial one (mean value 0.29 mm ± 0.25, P < 0.001). At ultrasound, the IFP was seen to be composed of very large lobules in the superficial part (mean area 0.29 cm2 ± 0.17 in extension), with a significant reduction in flexion (mean area 0.12 cm2 ± 0.07, P < 0.01). The deep lobules were smaller (mean area 0.11 cm2 ± 0.08 in extension) and did not change their values (mean area 0.19 cm2 ± 0.52 in flexion, P > 0.05). In the sagittal plane, the reduction of thickness of the superficial layer (with large adipose lobules) during flexion was 20.6%, whereas that of the deep layer (with small adipose lobules) was 1.3%. Numerical simulation of vertical loads, corresponding to flexion of the knee, showed that stress mainly developed within the interlobular septa and opposed bulging of the lobules. The characteristics of the lobular arrangement of the IFP (large lobules with superficial septa in the superficial part and small lobules with thick septa in the deep one), significant changes in the areas and perimeters of the superficial lobules, and the reduced thickness of the superficial layer during flexion all indicate the dynamic role played by the IFP in knee kinematics. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is the most common disabling joint disease throughout the world and its therapeutic effect is still not satisfactory in clinic nowadays. Recent studies showed that the exosomes derived from several types of mesenchymal stem cells (MSCs) could maintain chondrocyte homeostasis and ameliorate the pathological severity of OA in animal models, indicating that MSCs-derived exosomes could be a novel promising strategy for treating OA. In this study, we investigated the role and underlying mechanisms of infrapatellar fat pad (IPFP) MSCs-derived exosomes (MSCIPFP-Exos) on OA in vitro and in vivo. Our data revealed that MSCIPFP could produce amounts of MSCIPFP-Exos, which exhibited the typical morphological features of exosomes. The MSCIPFP-Exos ameliorated the OA severity in vivo and inhibited cell apoptosis, enhanced matrix synthesis and reduced the expression of catabolic factor in vitro. Moreover, MSCIPFP-Exos could significantly enhance autophagy level in chondrocytes partially via mTOR inhibition. Exosomal RNA-seq showed that the level of miR-100-5p that could bind to the 3′-untranslated region (3′UTR) of mTOR was the highest among microRNAs. MSCIPFP-Exos decreased the luciferase activity of mTOR 3′UTR, while inhibition of miR-100-5p could reverse the MSCIPFP-Exos-decreased mTOR signaling pathway. Intra-articular injection of antagomir-miR-100-5p dramatically attenuated MSCIPFP-Exos-mediated protective effect on articular cartilage in vivo. In brief, MSCIPFP-derived exosomes protect articular cartilage from damage and ameliorate gait abnormality in OA mice by maintaining cartilage homeostasis, the mechanism of which may be related to miR100-5p-regulated inhibition of mTOR-autophagy pathway. As it is relatively feasible to obtain human IPFP from OA patients by arthroscopic operation in clinic, MSCIPFP-derived exosomes may be a potential therapy for OA in the future. Image 1 [ABSTRACT FROM AUTHOR]

Aim: Osteoarthritis (OA) is a whole joint pathology involving cartilage, synovial membrane, meniscus, subchondral bone, and infrapatellar fat pad (IFP). Synovitis has been widely documented in OA suggesting its important role in pathogenesis. The aim of this study was to investigate the role of different joint tissues in promoting synovitis. Materials and methods: Conditioned media (CM) from cartilage, synovial membrane, meniscus, and IFP were generated from tissues of five patients undergoing total knee replacement and used to stimulate a human fibroblast-like synoviocytes cell line (K4IM). Cytokines, chemokines, and metalloproteases release was analyzed in all CM by Bio-Plex Assay and sulfated glycosaminoglycan (GAG) content by dimethylmethylene blue assay. Gene expression of several markers was evaluated by real-time PCR in K4IM cells stimulated with the CM obtained from joint tissues. Results: CM from all tissues produced high levels of IL-6, IL-8, and CCL2. CCL21, MMP-3, and −13 levels were detected in all CM except IFP. MMP-10 was present only in CM of cartilage and synovial tissues. IL-1β, IL-15, TNF-α, CCL5, and CCL19 were undetectable. However, only K4IM cells stimulated by the CM from OA synovium showed an increase of IL-6, CXCL-8, CCL21, MMP10, and IL-1β expression. Conclusion: Our study showed that K4IM might be a suitable in vitro model for evaluating different cellular pathways in OA studies. Importantly, we demonstrated that in OA, all joint tissues might be involved in the progression of synovitis with a predominant role of synovial membrane itself compared to the other joint tissues. [ABSTRACT FROM AUTHOR]

Abstract The aim of this study was to analyze the magnetic resonance imaging (MRI) volumetric and morphometric characteristics of the infrapatellar fat pad (IFP) and the suprapatellar fat pad (SFP) in normal controls, moderate and end-stage osteoarthritis (OA) patients. Forty-four MRI images of the three groups were collected: a) 17 patients undergoing meniscectomy with Outerbridge score 0 (control group); b) 15 patients undergoing meniscectomy with Outerbridge score 3/4 (moderate OA group); and c) 12 patients undergoing total knee replacement (end-stage OA group). Volume, depth, femoral and tibial arch lengths of IFP were quantified. The hypointense IFP signals were also scored. The SFP volume, oblique, antero-posterior and cranio-caudal lengths were determined. IFP and SFP characteristics were compared between groups. A decrease of IFP volume, depth, femoral, and tibial arch lengths in moderate and end-stage OA compared to controls were observed. A difference in IFP hypointense signal was found between groups. No differences were found in SFP characteristics between the groups. In controls and moderate OA patients, correlations were found among the different MRI characteristics of both IFP and SFP, while in the end-stage OA group correlations were found only in SFP. We evidenced differences of the IFP MRI morphometric characteristics between the groups analyzed, supporting an important role of IFP in OA pathology and progression. On the contrary, no differences were highlighted in SFP analysis suggesting that this fat pad is not clearly involved in OA, probably due to its peculiar localization and different function. [ABSTRACT FROM AUTHOR]

Purpose: There has been no specific study on the quantitative morphological changes that occur in the infrapatellar fat pad (IPFP) after anterior cruciate ligament (ACL) reconstruction. We used ultrasonography to evaluate the dynamics of the IPFP in knees after ACL reconstruction using the contralateral knees as controls.Methods: We enrolled 31 patients 3 months after they underwent ACL reconstruction. The thickness of the superficial part of the IPFP was measured using longitudinally oriented ultrasound images of the anterior part of both knees at 90° and 10° flexion. We then used these data to calculate the ratio of the change in thickness.Results: At 90° knee flexion, the superficial part of the IPFP was significantly thinner in the reconstructed knees (9.3 ± 3.4 mm) than in the contralateral knees (11.8 ± 4.6 mm). The thickness change ratio was significantly smaller in the reconstructed knees (188.6 ± 64.7%) than in the contralateral knees (249.7 ± 73.8%).Conclusion: When assessed 3 months after ACL reconstruction, the thickness of the superficial part of the IPFP at 90° knee flexion and the thickness change ratio of the IPFP were both significantly lower in the reconstructed knees than in the contralateral knees. [ABSTRACT FROM AUTHOR]

Adipose tissue is a rich source of stem cells, which are reported to represent 2% of the stromal vascular fraction (SVF). The infrapatellar fat pad (IFP) is a unique source of tissue, from which human adipose-derived stem cells (hADSCs) have been shown to harbour high chondrogenic potential. This review aims to calculate, based on the literature, the culture time needed before an average knee articular cartilage defect can be treated using stem cells obtained from arthroscopically or openly harvested IFP. Firstly, a systematic literature review was performed to search for studies that included the number of stem cells isolated from the IFP. Subsequent analysis was conducted to identify the amount of IFP tissue harvestable, stem cell count and the overall yield based on the harvesting method. We then determined the minimum time required before treating an average-sized knee articular cartilage defect with IFP-derived hADSCs by using our newly devised equation. The amount of fat tissue, the SVF cell count and the stem cell yield are all lower in arthroscopically harvested IFP tissue compared to that collected using arthrotomy. As an extrapolation, we show that an average knee defect can be treated in 20 or 17 days using arthroscopically or openly harvested IFP-derived hADSCs, respectively. In summary, the systematic review conducted in this study reveals that there is a higher amount of fat tissue, SVF cell count and overall yield (cells/volume or cells/gram) associated with open (arthrotomy) compared to arthroscopic IFP harvest. In addition to these review findings, we demonstrate that our novel framework can give an indication about the culture time needed to scale up IFP-derived stem cells for the treatment of articular cartilage defects based on harvesting method.

Cartilage repair by bone marrow derived mesenchymal stem cells (MSCs) can be influenced by inflammation in the knee. Next to synovium, the infrapatellar fat pad (IPFP) has been described as a source for inflammatory factors. Here, we investigated whether factors secreted by the IPFP affect chondrogenesis of MSCs and whether this is influenced by different joint pathologies or obesity. Furthermore, we examined the role of IPFP resident macrophages. First, we made conditioned medium from IPFP obtained from osteoarthritic joints, IPFP from traumatically injured joints during anterior cruciate ligament reconstruction, and subcutaneous adipose tissue. Additionally, we made conditioned medium of macrophages isolated from osteoarthritic IPFP and of polarised monocytes from peripheral blood. We evaluated the effect of different types of conditioned medium on MSC chondrogenesis. Conditioned medium from IPFP decreased collagen 2 and aggrecan gene expression as well as thionin and collagen type 2 staining. This anti-chondrogenic effect was the same for conditioned medium from IPFP of osteoarthritic and traumatically injured joints. Furthermore, IPFP from obese (Body Mass Index >30) donors did not inhibit chondrogenesis more than that of lean (Body Mass Index

Objective The purpose of our study was to assess soft tissue features of acute patellar tendon rupture on lateral knee radiograph that would facilitate early diagnosis. Methods The participants were divided into two groups of 35 patients each. There were 28 men and seven women with a mean age of 46 years in the control group and 26 men and nine women with a mean age of 47 years in the rupture group. The lateral knee radiograph of each patient was evaluated for Insall–Salvati ratio for patella alta, increased density of the infrapatellar fat pad, appearance of the soft tissue margin of the patellar tendon and bony avulsions. Results In the rupture group there were three consistent soft tissue radiographic features in addition to patellar alta. These were increased density of infrapatellar fat pad; loss of sharp, well‐defined linear margins of the patellar tendon and angulated wavy margin of the patellar tendon while in the control group these features were not observed. Conclusions The soft tissue radiographic features described in the rupture group are consistent and reliable. When coupled with careful clinical assessment, these will aid in early diagnosis and further imaging will be seldom required.

Fibrosis of the infrapatellar fat pad (IFP) occurs after knee joint surgery or during knee osteoarthritis (KOA) and causes persistent pain and limited mobility. Previous studies demonstrated that treating IFP fibrosis alleviated pain in animal models. In this study, we examined the effects of hyaluronic acid (HA) sheet transplantation on IFP fibrosis and articular cartilage degeneration in a monoiodoacetic acid (MIA) rat arthritis model (95 male rats). Rats received bilateral intra-articular MIA injections (1.0 mg/30 μL) and underwent surgery 4 days later. HA sheets were transplanted on the right knee of each rat (HA group), with the left knee receiving sham surgery (sham group). Incapacitance tests were performed at multiple time points up to 28 days after MIA injection. Macroscopic, histological, and immunohistochemical analyzes were performed 14 and 28 days after injection. The concentrations of HA and interleukin-1β (IL-1β) in the synovial fluid were measured using ELISA. Transplantation of HA sheets could alleviate persistent pain 10-28 days after injection. The HA sheets inhibited articular cartilage degeneration at 14 days. Fibrosis and the invasion of calcitonin gene-related peptide-positive nerve fiber endings in the IFP were inhibited at both 14 and 28 days. Moreover, the HA sheets remained histologically until 10 days after transplantation. The concentration of HA reached its peak on Day 10 after transplantation; the concentration of IL-1β in the sham group was significantly higher than that in the HA group on Day 7. Therefore, HA sheets could be a promising option to treat IFP fibrosis occurring in KOA and after knee joint surgery., (© 2023 Orthopaedic Research Society.)

Growing evidence indicates that infrapatellar fat pad (IPFP)-derived stem cells (IPFSCs) exert robust proliferation capacities and multilineage differentiation potentials. However, few papers summarize the advantages that the IPFP and IPFSCs have in regenerative medicine. In this review we delineate the development and anatomy of the IPFP by comparing it with an adjacent fibrous tissue, synovium, and a more frequently harvested fat depot, subcutaneous adipose tissue. Furthermore, we explore the similarities and differences of stem cells from these three tissues in terms of IPFSCs, synovium-derived stem cells and subcutaneous adipose tissue–derived stem cells in proliferation capacity and tri-lineage differentiation potentials, including chondrogenesis, osteogenesis and adipogenesis. Finally, we highlight the advantages of IPFSCs in regenerative medicine, such as the abundant accessibility and the ability to resist inflammation and senescence, two hurdles for cell-based tissue regeneration. Considering the comparative advantages of IPFSCs, the IPFP can serve as an excellent stem cell source for regenerative medicine, particularly for cartilage regeneration. [ABSTRACT FROM AUTHOR]

Purpose: The infrapatellar fat pad (IFP) is a common cause of knee pain and loss of knee flexion and extension. However, its anatomy and behavior are not consistently defined.Methods: Thirty-six unpaired fresh frozen knees (median age 34 years, range 21-68) were dissected, and IFP attachments and volume measured. The rectus femoris was elevated, suprapatellar pouch opened and videos recorded looking inferiorly along the femoral shaft at the IFP as the knee was flexed. The patellar retinacula were incised and the patella reflected distally. The attachment of the ligamentum mucosum (LMuc) to the intercondylar notch was released from the anterior cruciate ligament (ACL), both menisci and to the tibia via meniscotibial ligaments. IFP strands projecting along both sides of the patella were elevated and the IFP dissected from the inferior patellar pole. Magnetic resonance imaging (MRI) of one knee at ten flexion angles was performed and the IFP, patella, tibia and femur segmented.Results: In all specimens the IFP attached to the inferior patellar pole, femoral intercondylar notch (via the LMuc), proximal patellar tendon, intermeniscal ligament, both menisci and the anterior tibia via the meniscotibial ligaments. In 30 specimens the IFP attached to the anterior ACL fibers via the LMuc, and in 29 specimens it attached directly to the central anterior tibia. Proximal IFP extensions were identified alongside the patella in all specimens and visible on MRI [medially (100% of specimens), mean length 56.2 ± 8.9 mm, laterally (83%), mean length 23.9 ± 6.2 mm]. Mean IFP volume was 29.2 ± 6.1 ml. The LMuc, attached near the base of the middle IFP lobe, acting as a 'tether' drawing it superiorly during knee extension. The medial lobe consistently had a pedicle superomedially, positioned between the patella and medial trochlea. MRI scans demonstrated how the space between the anterior tibia and patellar tendon ('the anterior interval') narrowed during knee flexion, displacing the IFP superiorly and posteriorly as it conformed to the trochlear and intercondylar notch surfaces.Conclusion: Proximal IFP extensions are a novel description. The IFP is a dynamic structure, displacing significantly during knee motion, which is, therefore, vulnerable to interference from trauma or repetitive overload. Given that this trauma is often surgical, it may be appropriate that surgeons learn to minimize injury to the fat pad at surgery. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether infrapatellar fat pad (IPFP) signal intensity (SI) alteration predicts the occurrence of knee replacement (KR) in knee osteoarthritis (OA) patients over 5 years.Design: The subjects were selected from Osteoarthritis Initiative (OAI) study. Case knees (n = 127) were defined as those who received KR during 5 years follow-up visit. They were matched by gender, age and radiographic status with control knees (n = 127). We used T2-weighted MR images to measure IPFP SI alteration using a newly developed algorithm in MATLAB. The measurements were assessed at baseline (BL), T0 (the visit just before KR) and 1 year before T0 (T-1). Conditional logistic regression was used to analyse the associations between IPFP SI alterations and the risk of KR.Results: Participants were mostly female (57%), with an average age of 63.7 years old and a mean body mass index (BMI) of 29.5 kg/m2. In multivariable analysis, the standard deviation (SD) of IPFP SI [sDev (IPFP)] and the ratio of high SI region volume to whole IPFP volume [Percentage (H)] measured at BL were significantly associated with increased risks of KR after adjustment for covariates. IPFP SI alterations measured at T-1 including sDev (IPFP), Percentage (H) and clustering effect of high SI [Clustering factor (H)] were significantly associated with higher risks of KR. All measurements were significantly associated with higher risks of KR at T0.Conclusions: IPFP SI is associated with the occurrence of KR suggesting it may play a role in end-stage knee OA. [ABSTRACT FROM AUTHOR]

Abstract: The infrapatellar pad, a fibro‐adipose tissue with peculiar microscopic and mechanical features, is gaining wide attention in the field of rheumatological research. The purpose of this descriptive review is to summarize the most recent published evidence on the anatomic, physiologic and biomechanical inter‐relationship between the infrapatellar fat pad and the knee synovial membrane. As an extrasynovial tissue, the infrapatellar fat pad does not directly interact with the articular cartilage; based on its location in close contact with the synovial membrane, and due to the metabolic properties of adipose tissue, it may influence the behavior of the synovial membrane. In fact, considering evidence of macroscopic and microscopic anatomy, the infrapatellar fat pad is the site of insertion of the infrapatellar and medial synovial plicae. Also biochemically, there is much evidence highlighting the interaction among these two structures; in the case of inflammation, the mutual interplay is ascribable to the release of pro‐inflammatory mediators stimulating the proliferation of inflammatory cells and promoting tissue modifications in both. All these assumptions could support the emerging idea that the infrapatellar fat pad and the synovial membrane may be considered a morpho‐functional unit. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to investigate the relationship of patellofemoral joint morphology with infrapatellar fat pad edema and chondromalacia patella (CP) using patellar maltracking parameters on magnetic resonance imaging (MRI). Patients and methods: Between January 2010 and January 2013, 50 patients with edema in the superolateral portion of the infrapatellar fat pad (the study group) and control group (n=50) with a normal infrapatellar fat pad were identified on MRI to compare with regard to five patellar maltracking parameters retrospectively. These parameters were trochlear depth, the trochlear sulcus angle (TSA), patellar translation, the lateral patellofemoral angle (PFA), and the Insall-Salvati ratio. The relationship between patellar maltracking and the CP was also evaluated using the same parameters. Results: In the study group, the Insall-Salvati index and TSA were significantly higher (p=0.001), and the trochlear depth and PFA were low (p=0.001, p=0.01), while patellar translation showed no difference (p=0.957). In the CP group, the Insall-Salvati index and TSA were significantly high (p=0.001), the trochlear depth was low (p=0.001). No statistically significant difference was found in PFA and patellar translation (p=0.292, p=0.446). Conclusion: Our study results suggest that edema in the superolateral portion of infrapatellar fat pad and CP are associated with patellar maltracking. [ABSTRACT FROM AUTHOR]

OA is a complex disease involving mechanical, metabolic and inflammatory contributions to its aetiology. A key risk factor, obesity, is becoming an increasing focus of research due to its multiple potential impacts on OA incidence, progression and symptom severity. An increased load due to an increase in body mass has been well established as a mechanical contribution to the pathophysiology of OA. However, evidence of obesity-linked to OA in non-weight-bearing joints has implicated the biological role of adipose inflammation and metabolic abnormalities in OA. The identification of inflammatory mediators such as adipokines (adipose-derived molecules) in OA has further incriminated the role of adiposity. This narrative review aims to discuss the role of adipose-derived inflammation in OA, with a focus on the contrast between systemic and local adipose tissue, and potential treatment applications targeting the adipo-inflammatory aspects of the disease. [ABSTRACT FROM AUTHOR]