Regenerative Medicine and Microfragmented Adipose Tissue: The Emerging Role of Lipogems® in Pain Management and Tissue Repair

1. Introduction

Regenerative medicine represents a paradigm shift from symptom-oriented treatment to biologically driven restoration of tissue integrity and function [1]. This transition is particularly relevant in chronic pain and degenerative disorders, where conventional pharmacological and interventional strategies, such as nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, intra-articular corticosteroids and radiofrequency-based procedures, primarily target symptom control rather than the underlying biological drivers of disease. While these approaches may provide short-term analgesia, their long-term efficacy is often limited and they may be associated with significant adverse effects, including gastrointestinal, cardiovascular, and dependency-related risks [2,3].

In this context, adipose tissue has emerged as a central component of regenerative strategies due to its abundance, ease of harvesting and high content of mesenchymal stromal cells (MSCs), pericytes and bioactive mediators [4]. Compared with bone marrow-derived aspirates, adipose tissue yields a substantially higher number of progenitor cells per unit volume, enhancing its therapeutic potential in autologous applications [5]. Importantly, the regenerative capacity of adipose-derived products is increasingly understood to be mediated through paracrine signaling, immunomodulation and microenvironmental support rather than direct cellular differentiation [4,6].

Lipogems^® (Lipogems International SpA, Milan, Italy) is a closed, minimally manipulative system that processes lipoaspirate into microfragmented adipose tissue (MFAT) through gentle mechanical forces, preserving the native stromal vascular niche without enzymatic digestion [7]. This preservation of the perivascular architecture, including pericytes and extracellular matrix components, is hypothesized to enhance biological activity while maintaining compliance with regulatory definitions of minimal manipulation. Consequently, it occupies a unique translational position between advanced cell therapies and conventional injectables [8]. From a clinical perspective, the growing interest on it is driven by its dual potential to provide symptomatic relief and to modify disease processes [9]. Overall, it represents a promising regenerative approach that bridges the gap between purely symptomatic analgesia and disease-modifying interventions.

Several studies have attempted to compare MFAT with established analgesic interventions. For instance, observational and comparative studies in knee osteoarthritis suggest that MFAT may provide more sustained improvements in pain and function compared with intra-articular corticosteroids or hyaluronic acid [10]. In a prospective comparative study, Russo et al [11]. demonstrated that patients treated with MFAT exhibited clinically meaningful improvements in pain scores and functional outcomes that persisted beyond 6-12 months, exceeding the typical duration observed with corticosteroid injections. Similarly, Bruno et al [12]. reported that adipose-derived therapies, including MFAT, were associated with longer-lasting clinical benefits compared with conventional viscosupplementation, although heterogeneity among data limited definitive conclusions. Direct head-to-head randomized controlled trials remain scarce; however, emerging evidence suggests that MFAT may offer advantages over platelet-rich plasma (PRP) in certain contexts, particularly in more advanced degenerative conditions where a structural scaffold and sustained paracrine activity may be beneficial [13]. Conversely, PRP may demonstrate comparable or superior outcomes in early-stage disease, highlighting the importance of patient selection and disease phenotyping [14]. While preliminary comparative data are encouraging, there remains a critical need for high-quality randomized controlled trials directly comparing MFAT with standard-of-care treatments, including corticosteroids, hyaluronic acid, PRP, and emerging biologics, to better define its role within the evolving landscape of pain management and regenerative medicine.

Compared with systemic pharmacological analgesia, MFAT offers a fundamentally different therapeutic paradigm, targeting local inflammatory and degenerative processes while minimizing systemic exposure [15]. This is particularly relevant in elderly or comorbid populations, where the risk profile of chronic pharmacotherapy is substantial.

The growing clinical interest in MFAT and especially in Lipogems^® stems from its potential to provide a biologically active scaffold capable of delivering regenerative signals in situ. This review aims to synthesize current knowledge on MFAT, focusing on Lipogems^®, and to critically appraise its role in regenerative medicine and pain management.

2. Methods

This narrative review was conducted in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA), ensuring methodological transparency, comprehensive literature coverage, and critical appraisal of the available evidence [16]. Although narrative in nature, particular attention was paid to minimizing selection and interpretative bias through a structured and reproducible search strategy, explicit eligibility criteria, and rigorous source verification.

Literature Search Strategy

A comprehensive literature search was performed across the following electronic databases: PubMed/MEDLINE, EMBASE, Web of Science, and Scopus. The search covered the period from January 2005 to March 2026, in order to capture both foundational studies on adipose-derived regenerative therapies and the most recent clinical applications of MFAT, including Lipogems^®.

The literature search strategy was designed to ensure both sensitivity and specificity by integrating controlled vocabulary (e.g., MeSH terms) with free-text keywords. Core search strings targeted key concepts related to microfragmented adipose tissue and regenerative medicine, including combinations such as “Lipogems” or “microfragmented adipose tissue” with “regenerative medicine”, “tissue repair,” and “mesenchymal stromal cells”. Additional queries focused on adipose-derived cellular therapies in relation to pain conditions, including “chronic pain”, “osteoarthritis”, and “tendinopathies”, as well as “clinical applications” in “musculoskeletal and orthopedic settings”. Comparative effectiveness was explored through searches combining “regenerative therapies” with established interventions such as “PRP”, “corticosteroids”, and “hyaluronic acid”. Boolean operators and truncation strategies were adapted to each database. To enhance completeness, manual screening of reference lists from relevant studies and reviews was also performed.

Eligibility Criteria

Studies were deemed eligible if they were peer-reviewed publications indexed in major biomedical databases and included clinical (randomized or non-randomized), translational, or preclinical investigations focusing on MFAT, Lipogems^®, or adipose-derived regenerative therapies. Eligible studies were required to report outcomes related to pain, functional improvement, tissue repair, or underlying biological mechanisms, and to be published in English. Exclusion criteria comprised conference abstracts without full-text availability, non-peer-reviewed sources, studies with insufficient methodological transparency, and secondary citations lacking access to original data.

Study Selection and Data Extraction

Titles and abstracts were screened for relevance by 3 independent authors (YVT, PVP and MNE), followed by full-text evaluation of potentially eligible studies. Data extraction focused on study design, patient population, intervention characteristics (including processing techniques), comparator groups where available, outcome measures, follow-up duration and key findings.

Quality Appraisal and Synthesis

In line with SANRA recommendations, the methodological quality of included studies was appraised qualitatively, with emphasis on study design robustness, sample size, consistency of outcome measures, and transparency of reporting. Particular attention was given to the identification of comparative studies evaluating MFAT against established analgesic or regenerative interventions (e.g., corticosteroids, hyaluronic acid, platelet-rich plasma).

The synthesis was conducted using a thematic and mechanistic approach, integrating biological rationale with clinical evidence to provide a coherent translational perspective. Potential sources of bias, heterogeneity and limitations in the current literature were explicitly acknowledged throughout the review.

3. Biological Rationale of MFAT

Cellular Composition and Structural Preservation

Adipose tissue is a highly complex and heterogeneous organ composed of adipocytes, endothelial cells, immune cells, pericytes, and mesenchymal stromal/stem cells (MSCs), all embedded within a dynamic extracellular matrix (ECM) that provides structural support and biochemical signaling [17]. Within this milieu, the stromal vascular fraction (SVF) represents a critical functional compartment, orchestrating regenerative processes primarily through paracrine signaling, extracellular vesicle release, and immunomodulatory interactions rather than direct cellular differentiation [18]. This paradigm has been increasingly reinforced by recent translational studies highlighting the central role of the adipose secretome, including cytokines, growth factors and exosomes, in modulating inflammation and promoting tissue repair [19].

In contrast to enzymatic digestion techniques, which disrupt cellular architecture and may alter cell phenotype, the Lipogems^® system employs gentle mechanical processing to preserve the structural integrity of adipose tissue clusters [7,20]. This approach maintains the native stromal vascular niche, resulting in a MFAT product enriched in pericyte-like cells and MSC precursors that remain embedded within their physiological microenvironment. The preservation of ECM components and microvascular structures is increasingly recognized as a key determinant of regenerative efficacy, as it facilitates cell-cell communication and sustains a bioactive scaffold capable of prolonged paracrine activity [21,22]. Pericytes, localized along the abluminal surface of microvessels, are now widely considered progenitors of MSCs and play a central role in angiogenesis, vascular stability, and tissue regeneration [23]. Their retention within MFAT is hypothesized to enhance therapeutic potential by enabling a context-dependent activation into MSC-like phenotypes in response to local injury signals. More recent evidence further suggests that pericyte-immune cell crosstalk contributes to macrophage polarization and modulation of the inflammatory microenvironment, thereby linking vascular biology with immune-mediated repair mechanisms [24]. Additionally, emerging studies have emphasized the importance of extracellular vesicles and exosomes derived from adipose tissue as critical mediators of regenerative signaling, capable of influencing gene expression, angiogenesis, and anti-fibrotic pathways [25]. Collectively, these advances support the concept that MFAT represents not merely a cellular therapy but a structurally preserved, biologically active microenvironment that integrates cellular, matrix, and paracrine components to optimize regenerative outcomes.

Paracrine Signaling and Secretome

As already exposed, the therapeutic efficacy of MFAT is now widely understood to be predominantly mediated through paracrine and trophic mechanisms rather than direct engraftment or differentiation of transplanted cells. MSCs, together with pericytes and other components of the stromal vascular niche, secrete a complex and dynamic repertoire of bioactive molecules, including cytokines, chemokines, growth factors, and extracellular vesicles (EVs), which collectively orchestrate tissue repair and immunomodulation [26]. Among the most relevant mediators are vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), transforming growth factor-β (TGF-β), and interleukin-10 (IL-10), all of which contribute to angiogenesis, anti-inflammatory signaling, and extracellular matrix remodeling.

More recent and well-controlled studies have further highlighted the central role of extracellular vesicles and exosomes as key effectors of MSC function, capable of transferring microRNAs, proteins, and lipids that modulate gene expression in target cells and promote regenerative pathways [27]. This EV-mediated communication is increasingly recognized as a critical mechanism underlying the sustained biological activity of MFAT [28]. Importantly, these paracrine signals facilitate a shift from a pro-inflammatory to an anti-inflammatory microenvironment, characterized by macrophage polarization toward an M2 phenotype and attenuation of cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) [29]. Such immunological reprogramming is particularly relevant in chronic pain states, where persistent low-grade inflammation and neuroimmune dysregulation play a central pathogenic role [30]. These insights reinforce the concept of MFAT as a biologically active signaling platform capable of modulating local tissue environments and promoting functional recovery.

Immunomodulatory Effects

MFAT exerts significant immunomodulatory effects through complex interactions with both innate and adaptive immune systems, influencing macrophage polarization, T-cell activity, and the broader cytokine milieu [31]. Along with the paracrine effect promoting macrophage polarization toward an M2 anti-inflammatory phenotype, which supports anti-inflammatory responses, tissue repair and remodeling [32,33], this transition is associated with the downregulation of key pro-inflammatory mediators, such as TNF-α and IL-1β, and the upregulation of anti-inflammatory cytokines, including IL-10 and TGF-β. More recent and well-controlled studies have further demonstrated that this immunological reprogramming is mediated not only by soluble factors but also by extracellular vesicles and microRNA signaling, which modulate gene expression in immune and stromal cells [34]. Additionally, MFAT has been shown to influence T-cell proliferation and regulatory T-cell induction, contributing to immune tolerance and resolution of chronic inflammation [35]. These mechanisms closely align with contemporary models of chronic pain, which increasingly emphasize the role of neuroimmune crosstalk, peripheral sensitization, and central immune activation in the persistence of pain states [36].

4. Mechanisms of Action in Tissue Repair and Pain Modulation

Anti-Inflammatory Effects

Chronic musculoskeletal disorders, including osteoarthritis, are increasingly recognized as conditions driven not only by structural degeneration but also by persistent, low-grade inflammation within the joint microenvironment [37]. Synovial inflammation, activation of innate immune pathways, and the release of catabolic mediators contribute to cartilage degradation, subchondral bone remodeling, and the sensitization of peripheral nociceptors [38]. In this context, inflammation represents a central mechanistic link between tissue damage and pain generation, reinforcing the need for therapeutic strategies that extend beyond purely symptomatic analgesia. MFAT has demonstrated the capacity to modulate this inflammatory milieu through a multifaceted biological action (Figure 1). Experimental and clinical evidence indicates that MFAT downregulates key articular pro-inflammatory cytokines (TNF-α and IL-1β) and induces microRNA-mediated suppression of nuclear factor-κB (NF-κB) signaling and other inflammatory pathways implicated in osteoarthritis progression [39]. Importantly, these anti-inflammatory effects are closely linked to modulation of neuroimmune interactions, which are now understood to play a critical role in pain chronification [36]. By attenuating synovial inflammation and reducing the release of algogenic substances, MFAT may contribute not only to structural tissue preservation but also to the reduction of peripheral sensitization and nociceptive input [40]. This positions MFAT as a biologically coherent intervention within contemporary models of pain, where inflammation is both a driver of tissue pathology and a key determinant of pain persistence.

Angiogenesis and Tissue Regeneration

The promotion of neovascularization represents a fundamental prerequisite for effective tissue repair and regeneration, as adequate vascular supply is essential for oxygen delivery, nutrient exchange, and the removal of metabolic waste [41]. In degenerative and chronically inflamed tissues, impaired microcirculation and endothelial dysfunction contribute to a hostile microenvironment that limits intrinsic healing capacity [42]. Within this context, MFAT has emerged as a biologically active substrate capable of enhancing angiogenic processes through multiple coordinated mechanisms [43]. MFAT-derived cells and their secretome release a broad spectrum of pro-angiogenic factors, including vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and angiopoietins, which collectively stimulate endothelial cell proliferation, migration, and capillary network formation (Figure 1) [17,44]. In addition to these soluble mediators, more recent and well-controlled studies have emphasized the role of extracellular vesicles and exosome-associated microRNAs in regulating endothelial gene expression, thereby promoting sustained angiogenic signaling [45]. The preservation of perivascular niches within MFAT further supports vascular regeneration by maintaining pericyte-endothelial interactions, which are critical for vessel stabilization and maturation [46].

Importantly, enhanced neovascularization not only facilitates structural repair but also contributes to functional recovery by improving tissue perfusion and modulating local inflammatory responses. Emerging evidence suggests that improved microvascular integrity may indirectly influence nociceptive processing by reducing ischemia-induced sensitization and limiting the release of algogenic mediators [47]. All these findings position MFAT as a promising therapeutic approach that integrates angiogenic, immunomodulatory and regenerative mechanisms within a unified biological framework.

Extracellular Matrix Remodeling

MFAT contributes to extracellular matrix remodeling through the regulated secretion of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), thereby maintaining a balanced turnover between matrix degradation and synthesis [48]. Recent studies highlight the role of adipose-derived stromal cells in modulating MMP/TIMP dynamics, supporting controlled tissue repair and limiting fibrosis [49,50].

The extracellular matrix (ECM) is a dynamic network of macromolecules that provides structural support, regulates cellular behavior and serves as a reservoir for signaling molecules (Figure 1) [48]. Its homeostasis depends on a balance between synthesis and degradation, primarily regulated by MMPs and TIMPs [51]. Disruption of this balance, as observed in osteoarthritis and other chronic conditions, leads to pathological remodeling characterized by excessive degradation or fibrosis [52,53]. In osteoarthritis, this catabolic shift is driven by increased activity of MMPs and aggrecans, amplified by pro-inflammatory cytokines such as TNF-α and IL-1β, alongside insufficient TIMP activity, resulting in progressive cartilage damage [54,55,56]. MFAT exerts a modulatory effect on ECM remodeling through multiple mechanisms. Adipose-derived stromal cells regulate MMP/TIMP dynamics, reducing matrix degradation and promoting tissue repair, while enhancing collagen synthesis via paracrine and juxtacrine signaling [49,50,57]. Experimental models show that MFAT reduces degradative mediators such as MMP-9, increases TIMP-1, and downregulates inflammatory pathways including TLR4 and NF-κB, thereby attenuating ECM breakdown [35,58]. A key mechanism involves EVs released by adipose-derived MSCs, which carry bioactive molecules capable of modulating gene expression and ECM turnover [59]. These EVs promote matrix reconstruction, regulate collagen balance and exert anti-fibrotic effects through pathways such as ERK/MAPK and miRNA-mediated signaling, including miR-192-5p targeting the IL-17RA/Smad axis [60,61].

Proteomic and miRNA analyses further highlight MFAT’s cartilage-protective profile, including promotion of anti-inflammatory macrophage polarization [62]. Clinically, MFAT injections have been associated with increased glycosaminoglycan content in cartilage, suggesting enhanced matrix regeneration [63]. Additionally, inflammatory priming may further enhance the anti-fibrotic and remodeling capacity of MFAT, supporting a context-dependent therapeutic effect [49].

Neuro-Modulatory Effects

Emerging evidence indicates that adipose-derived products can modulate nociceptive pathways by attenuating neuroinflammation and reducing peripheral nerve sensitization [38,64]. These effects are mediated through cytokine regulation, glial cell modulation, and extracellular vesicle signaling. Recent well-controlled studies further support their role in influencing neuroimmune interactions and pain processing, positioning MFAT as a promising therapeutic strategy in mixed pain conditions characterized by overlapping nociceptive and neuropathic mechanisms [65,66].

As previously reported, emerging evidence suggests that adipose-derived products modulate nociceptive pathways by attenuating neuroinflammation and reducing peripheral sensitization [38,64]. Chronic pain is driven by maladaptive neuroimmune interactions, in which activated glial cells release pro-inflammatory mediators that sustain central sensitization and neuronal hyperexcitability [67,68,69]. Adipose-derived MSCs and stromal components within MFAT counteract these processes through multiple mechanisms. Preclinical studies show reversal of nociceptive hypersensitivity and reduction of inflammatory cytokines (e.g., TNF-α, IL-6), partly via modulation of microglial polarization toward an anti-inflammatory M2 phenotype [70,71,72]. EVs further contribute to neuromodulation by delivering bioactive molecules across neural barriers, promoting nerve repair, neurite growth and upregulation of neurotrophic factors such as BDNF, NGF and GDNF [73,74,75,76]. Additionally, the adipose-derived secretome suppresses microglial activation and modulates purinergic signaling, supporting pain reduction [77,78]. MFAT also exerts antioxidant effects, reducing reactive oxygen species and restoring redox balance, thereby limiting neuronal hyperexcitability associated with neuropathic pain [79,80]. By targeting neuroinflammation, glial activation, neurotrophic support, and oxidative stress, MFAT represents a multimodal approach to pain modulation in mixed pain conditions [65,66], although further translational studies are needed to clarify underlying mechanisms and optimize clinical use (Table 1).

Table 1. Biological Mechanisms of Micro-Fragmented Adipose Tissue (MFAT) Relevant to Pain Modulation and Tissue Repair.

Mechanism Domain	Study Type	Reported Biological Effects	Proposed Mechanism of Pain Modulation	Ref
Cellular Architecture & Perivascular Niche Preservation	In vivo In vitro SR/MA	MAT pericyte fraction 33.5% vs LPA 8.39%; enzymatic dissociation abolished secretory advantage. WBC –79%, RBC –76% after microfragmentation; stromal proportions preserved. CD146+CD34–CD45– pericytes 14.6%±1.02% of SVF; clonal multipotency confirmed†. SMF/Lipogems grafts enriched in pericytes + ↑VEGF vs centrifuged fat. Lipogems filtration bag retains intact microvascular clusters	Intact perivascular niche may sustain prolonged paracrine signalling; 3D scaffold may act as sustained-release depot, potentially attenuating peripheral nociceptor sensitisation.	[20,21,22,23,62]
Immune modulation & Macrophage Polarization	In vitro In vivo Mechanistic/ Review	MFAT co-culture with OA synoviocytes: CCL2↓, CCL3↓, CCL5↓, MMP-9, IL-10↑, PGE₂↑; miR-92a-3p → KLHL29 suppression confirmed by luciferase assay. MFAT-CM fully attenuated LPS-induced IL-1β and IL-6 in U937 macrophages, IL-1Rα, TGF-β1/β3, MIF progressively ↑ D1→D5. MSC-mediated M1→M2 shift via CARD9–NF-κB pathway demonstrated in in vivo MSC models†.	M1→M2 shift and cytokine attenuation may reduce synovial pro-algesic signalling, potentially decreasing peripheral sensitisation and nociceptor activation in OA joints.	[32,33,34,35,54,67,81]
Paracrine Secretome & Extracellular Vesicles (EVs)	In vitro Mechanistic/ Review	MAT secretes quantitatively more growth factors/cytokines than SVF; enzymatic dissociation abolishes secretory advantage. 376/381 EV-miRNAs detected; μFAT-enriched subset corresponds to ASC-EV-specific miRNAs (proteomics confirmed). MFAT-CM: IL-1Rα, TGF-β1/β3, MIF ↑ D1→D5; HGF stable. ASC-secretome proteomic analysis: 101 immune-regulatory factors identified†.	Intact 3D scaffold may function as sustained paracrine depot; secreted factors and EV-miRNA cargo may modulate immune, angiogenic, and neuroprotective pathways, potentially contributing to multimodal analgesic and regenerative effects.	[19,20,25,27,34,62,77,81]
Angiogenesis & Microvascular Remodeling	SR/MA In vitro Mechanistic Review	MFAT-CM → tube-like structure formation in BAECs (3/5 wells at 24 h → 5/5 at 5 d); p-ERK1/2 ↑. AT-MSC secretome ↑ HUVEC branching ×2.24 normoxia and ×2.44 hypoxia; significant in both HUVEC and RAEC models†. SMF grafts: enriched pericyte fraction + ↑VEGF vs centrifuged fat; improved graft retention in animal models.	MFAT paracrine factors may activate VEGFR2/ p-ERK1/2 in resident endothelial cells, potentially facilitating neovascularisation; preserved pericytes may stabilise capillaries and restore microcirculation, consistent with attenuation of ischaemia-driven peripheral sensitisation.	[17,21,41,43,44,46,81]
Extracellular Matrix (ECM) Remodeling	In vitro In vivo Mechanistic/ Review Observational	Intra-articular MFAT: dGEMRIC GAG ↑ in 53.6% of 224 joint facets at 12 mo; deterioration in only 11.2%; VAS rest 3.94→0.56, VAS movement 7.33→3.17; no chondrotoxicity (n=17, 32 knees). ASC paracrine → collagen I (PRO-C1) ↑; juxtacrine → collagen VI ↑; TGF-β upregulated 18 ECM transcripts (COL1A1/A2, COL3A1, FN1, LOX1, POSTN, XYLT1)†. MFAT-CM: MMP-9↓, TIMP-1↑ in OA synoviocytes.	ASC-secreted TGF-β1/TIMP-1 may shift MMP/TIMP balance toward matrix preservation, potentially attenuating aggrecan degradation; proteoglycan restoration is consistent with reduced subchondral mechanosensitisation and nociceptor sensitisation.	[35,48,51,52,53,55,56,57,60,63]
Neuroprotection & Neuroinflammation Attenuation	In vivo In vitro Mechanistic Review	IV hASC (1×10⁶, CCI model): complete thermal hyperalgesia reversal at day 1; IL-1β ↓ to sham levels in sciatic nerve by day 3; IL-10 ↑ progressively; iNOS fully restored at L4–L6 spinal cord at 14 d†. hASC-CM (MIA-OA mice): rapid antihyperalgesic + antiallodynic effect via IV/IA/IPL; DRG/spinal cord neuroinflammatory markers ↓ by RT-qPCR; 101 immune-regulatory secretome factors (mass spectrometry)†. AdMSC co-culture with rat SDH: LPS-induced TNFα↓, IL-6↓; NFκB nuclear translocation↓ in microglia; IL-10↑, TGF-β, TSG-6 expressed†. ADSC-Exo: Schwann cell apoptosis↓; Bcl-2↑, Bax↓; proliferation ↑ in SNI model†.	ASC secretome/ EVs may suppress microglial/astrocyte activation in DRG and dorsal horn, potentially reducing NFκB-driven neuroinflammation and central sensitisation; EV-mediated Schwann cell survival may preserve peripheral nerve integrity, attenuating ongoing nociceptive input.	[24,67,68,69,70,71,72,73,74,75,77,82]
Study Type categories:SR/MA = Systematic review or meta-analysis; RCT = Randomized controlled trial; Controlled clinical = Non-randomized study with comparator; Observational clinical = Case series, cohort, before-after without control; Preclinical (in vivo) = Animal models; Preclinical (in vitro) = Cell culture, explant, organoid † General MSC/ASC/SVF study; findings not specific to MFAT/Lipogems® Abbreviations: ASC: adipose-derived stromal/stem cell; AdMSC: adipose-derived mesenchymal stem cell; AT-MSC: adipose tissue–derived mesenchymal stromal cell; BAEC: bovine aortic endothelial cell; Bax: BCL2-associated X protein; Bcl-2: B-cell lymphoma 2; CARD9: caspase recruitment domain-containing protein 9; CCI: chronic constriction injury; CCL: C-C motif chemokine ligand; CD: cluster of differentiation; CM: conditioned medium; COL: collagen; dGEMRIC: delayed gadolinium-enhanced MRI of cartilage; DRG: dorsal root ganglion; ECM: extracellular matrix; ERK1/2: extracellular signal-regulated kinase 1/2; EV: extracellular vesicle; FN1: fibronectin 1; GAG: glycosaminoglycan; hASC: human adipose-derived stromal/stem cell; HGF: hepatocyte growth factor; HUVEC: human umbilical vein endothelial cell; IA: intra-articular; IL: interleukin; IL-1Rα: interleukin-1 receptor antagonist; iNOS: inducible nitric oxide synthase; IPL: intraplantar; IV: intravenous; KLHL29: kelch-like protein 29; LOX1: lysyl oxidase 1; LPA: lipoaspirate; LPS: lipopolysaccharide; MAT: microfragmented adipose tissue; MFAT: microfragmented adipose tissue; MFAT-CM: microfragmented adipose tissue–conditioned medium; MIF: macrophage migration inhibitory factor; MIA: monosodium iodoacetate; miRNA: microRNA; MMP: matrix metalloproteinase; MSC: mesenchymal stromal/stem cell; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NG2: neural/glial antigen 2; OA: osteoarthritis; PDGF: platelet-derived growth factor; PDGFR-β: platelet-derived growth factor receptor beta; PGE₂: prostaglandin E₂; POSTN: periostin; RAEC: rat aortic endothelial cell; RANTES: regulated on activation, normal T cell expressed and secreted (CCL5); RBC: red blood cell; RCT: randomized controlled trial; RT-qPCR: reverse transcription quantitative polymerase chain reaction; SDH: spinal dorsal horn; SMF: stromal microfragmented fat; SNI: spared nerve injury; SR/MA: systematic review and meta-analysis; SVF: stromal vascular fraction; TGF-β: transforming growth factor beta; TIMP: tissue inhibitor of metalloproteinases; TNF-α: tumor necrosis factor alpha; TSG-6: tumor necrosis factor-stimulated gene 6 protein; VAS: Visual Analogue Scale; VEGF: vascular endothelial growth factor; VEGFR2: vascular endothelial growth factor receptor 2; WBC: white blood cell; XYLT1: xylosyltransferase 1.

Table 1. Biological Mechanisms of Micro-Fragmented Adipose Tissue (MFAT) Relevant to Pain Modulation and Tissue Repair.

Mechanism Domain	Study Type	Reported Biological Effects	Proposed Mechanism of Pain Modulation	Ref
Cellular Architecture & Perivascular Niche Preservation	In vivo In vitro SR/MA	MAT pericyte fraction 33.5% vs LPA 8.39%; enzymatic dissociation abolished secretory advantage. WBC –79%, RBC –76% after microfragmentation; stromal proportions preserved. CD146+CD34–CD45– pericytes 14.6%±1.02% of SVF; clonal multipotency confirmed†. SMF/Lipogems grafts enriched in pericytes + ↑VEGF vs centrifuged fat. Lipogems filtration bag retains intact microvascular clusters	Intact perivascular niche may sustain prolonged paracrine signalling; 3D scaffold may act as sustained-release depot, potentially attenuating peripheral nociceptor sensitisation.	[20,21,22,23,62]
Immune modulation & Macrophage Polarization	In vitro In vivo Mechanistic/ Review	MFAT co-culture with OA synoviocytes: CCL2↓, CCL3↓, CCL5↓, MMP-9, IL-10↑, PGE₂↑; miR-92a-3p → KLHL29 suppression confirmed by luciferase assay. MFAT-CM fully attenuated LPS-induced IL-1β and IL-6 in U937 macrophages, IL-1Rα, TGF-β1/β3, MIF progressively ↑ D1→D5. MSC-mediated M1→M2 shift via CARD9–NF-κB pathway demonstrated in in vivo MSC models†.	M1→M2 shift and cytokine attenuation may reduce synovial pro-algesic signalling, potentially decreasing peripheral sensitisation and nociceptor activation in OA joints.	[32,33,34,35,54,67,81]
Paracrine Secretome & Extracellular Vesicles (EVs)	In vitro Mechanistic/ Review	MAT secretes quantitatively more growth factors/cytokines than SVF; enzymatic dissociation abolishes secretory advantage. 376/381 EV-miRNAs detected; μFAT-enriched subset corresponds to ASC-EV-specific miRNAs (proteomics confirmed). MFAT-CM: IL-1Rα, TGF-β1/β3, MIF ↑ D1→D5; HGF stable. ASC-secretome proteomic analysis: 101 immune-regulatory factors identified†.	Intact 3D scaffold may function as sustained paracrine depot; secreted factors and EV-miRNA cargo may modulate immune, angiogenic, and neuroprotective pathways, potentially contributing to multimodal analgesic and regenerative effects.	[19,20,25,27,34,62,77,81]
Angiogenesis & Microvascular Remodeling	SR/MA In vitro Mechanistic Review	MFAT-CM → tube-like structure formation in BAECs (3/5 wells at 24 h → 5/5 at 5 d); p-ERK1/2 ↑. AT-MSC secretome ↑ HUVEC branching ×2.24 normoxia and ×2.44 hypoxia; significant in both HUVEC and RAEC models†. SMF grafts: enriched pericyte fraction + ↑VEGF vs centrifuged fat; improved graft retention in animal models.	MFAT paracrine factors may activate VEGFR2/ p-ERK1/2 in resident endothelial cells, potentially facilitating neovascularisation; preserved pericytes may stabilise capillaries and restore microcirculation, consistent with attenuation of ischaemia-driven peripheral sensitisation.	[17,21,41,43,44,46,81]
Extracellular Matrix (ECM) Remodeling	In vitro In vivo Mechanistic/ Review Observational	Intra-articular MFAT: dGEMRIC GAG ↑ in 53.6% of 224 joint facets at 12 mo; deterioration in only 11.2%; VAS rest 3.94→0.56, VAS movement 7.33→3.17; no chondrotoxicity (n=17, 32 knees). ASC paracrine → collagen I (PRO-C1) ↑; juxtacrine → collagen VI ↑; TGF-β upregulated 18 ECM transcripts (COL1A1/A2, COL3A1, FN1, LOX1, POSTN, XYLT1)†. MFAT-CM: MMP-9↓, TIMP-1↑ in OA synoviocytes.	ASC-secreted TGF-β1/TIMP-1 may shift MMP/TIMP balance toward matrix preservation, potentially attenuating aggrecan degradation; proteoglycan restoration is consistent with reduced subchondral mechanosensitisation and nociceptor sensitisation.	[35,48,51,52,53,55,56,57,60,63]
Neuroprotection & Neuroinflammation Attenuation	In vivo In vitro Mechanistic Review	IV hASC (1×10⁶, CCI model): complete thermal hyperalgesia reversal at day 1; IL-1β ↓ to sham levels in sciatic nerve by day 3; IL-10 ↑ progressively; iNOS fully restored at L4–L6 spinal cord at 14 d†. hASC-CM (MIA-OA mice): rapid antihyperalgesic + antiallodynic effect via IV/IA/IPL; DRG/spinal cord neuroinflammatory markers ↓ by RT-qPCR; 101 immune-regulatory secretome factors (mass spectrometry)†. AdMSC co-culture with rat SDH: LPS-induced TNFα↓, IL-6↓; NFκB nuclear translocation↓ in microglia; IL-10↑, TGF-β, TSG-6 expressed†. ADSC-Exo: Schwann cell apoptosis↓; Bcl-2↑, Bax↓; proliferation ↑ in SNI model†.	ASC secretome/ EVs may suppress microglial/astrocyte activation in DRG and dorsal horn, potentially reducing NFκB-driven neuroinflammation and central sensitisation; EV-mediated Schwann cell survival may preserve peripheral nerve integrity, attenuating ongoing nociceptive input.	[24,67,68,69,70,71,72,73,74,75,77,82]
Study Type categories:SR/MA = Systematic review or meta-analysis; RCT = Randomized controlled trial; Controlled clinical = Non-randomized study with comparator; Observational clinical = Case series, cohort, before-after without control; Preclinical (in vivo) = Animal models; Preclinical (in vitro) = Cell culture, explant, organoid † General MSC/ASC/SVF study; findings not specific to MFAT/Lipogems® Abbreviations: ASC: adipose-derived stromal/stem cell; AdMSC: adipose-derived mesenchymal stem cell; AT-MSC: adipose tissue–derived mesenchymal stromal cell; BAEC: bovine aortic endothelial cell; Bax: BCL2-associated X protein; Bcl-2: B-cell lymphoma 2; CARD9: caspase recruitment domain-containing protein 9; CCI: chronic constriction injury; CCL: C-C motif chemokine ligand; CD: cluster of differentiation; CM: conditioned medium; COL: collagen; dGEMRIC: delayed gadolinium-enhanced MRI of cartilage; DRG: dorsal root ganglion; ECM: extracellular matrix; ERK1/2: extracellular signal-regulated kinase 1/2; EV: extracellular vesicle; FN1: fibronectin 1; GAG: glycosaminoglycan; hASC: human adipose-derived stromal/stem cell; HGF: hepatocyte growth factor; HUVEC: human umbilical vein endothelial cell; IA: intra-articular; IL: interleukin; IL-1Rα: interleukin-1 receptor antagonist; iNOS: inducible nitric oxide synthase; IPL: intraplantar; IV: intravenous; KLHL29: kelch-like protein 29; LOX1: lysyl oxidase 1; LPA: lipoaspirate; LPS: lipopolysaccharide; MAT: microfragmented adipose tissue; MFAT: microfragmented adipose tissue; MFAT-CM: microfragmented adipose tissue–conditioned medium; MIF: macrophage migration inhibitory factor; MIA: monosodium iodoacetate; miRNA: microRNA; MMP: matrix metalloproteinase; MSC: mesenchymal stromal/stem cell; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NG2: neural/glial antigen 2; OA: osteoarthritis; PDGF: platelet-derived growth factor; PDGFR-β: platelet-derived growth factor receptor beta; PGE₂: prostaglandin E₂; POSTN: periostin; RAEC: rat aortic endothelial cell; RANTES: regulated on activation, normal T cell expressed and secreted (CCL5); RBC: red blood cell; RCT: randomized controlled trial; RT-qPCR: reverse transcription quantitative polymerase chain reaction; SDH: spinal dorsal horn; SMF: stromal microfragmented fat; SNI: spared nerve injury; SR/MA: systematic review and meta-analysis; SVF: stromal vascular fraction; TGF-β: transforming growth factor beta; TIMP: tissue inhibitor of metalloproteinases; TNF-α: tumor necrosis factor alpha; TSG-6: tumor necrosis factor-stimulated gene 6 protein; VAS: Visual Analogue Scale; VEGF: vascular endothelial growth factor; VEGFR2: vascular endothelial growth factor receptor 2; WBC: white blood cell; XYLT1: xylosyltransferase 1.

5. Conclusions

MFAT, including the one delivered through the Lipogems^® system, represents a promising and biologically sound approach in regenerative medicine. Its ability to modulate inflammation, promote tissue repair, and potentially influence pain pathways positions it as a valuable tool in the management of musculoskeletal and chronic pain conditions. Future research should focus on methodological rigor, mechanistic elucidation, and integration into personalized treatment paradigms to fully realize its clinical potential.