3.4.1 VAS, KOOS and WOMAC at 6 months, 12 months and 24 months post procedure

Five studies assessed pain scores associated with ADMSC and SVF treatments relative to baseline.¹,²,⁶,⁹,¹⁰ Two observational studies² and two RCTs⁸,⁹ provided direct VAS and WOMAC data, while Aletto et al.’s systematic review¹ synthesised findings from three studies, including one VAS pain score and three WOMAC scores specific to SVF.

Fig. 3 illustrates pain improvement from baseline at 6-, 12-, and 24-months using outcome measures such as the Visual Analog Scale (VAS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Knee Injury and Osteoarthritis Outcome Score (KOOS). Additionally, Fig. 4 highlights individual contributions and variations between ADMSC and SVF interventions, with studies from Aletto et al.¹ individually colour coded.

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Fig. 4 Prolonged efficacy of ADMSC and SVF visualized by pain Score (VAS, WOMAC, KOOS) improvement within a period of 6 mos, 12 mos & 24 mos.

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VAS scores assessing pain intensity showed significant reductions over time in both ADMSC and SVF groups (Fig. 4). Kim J et al.⁶ reported substantial pain improvement in the ADMSC group by 24 months (mean improvement: 16.92), while Rogers et al.⁸ observed notable VAS score improvements for SVF at 12 months (mean improvement: 18.10). Across studies, ADMSC demonstrated slightly greater long-term benefits by 24 months. Both treatments showed low variability in outcomes, indicating consistent efficacy.

WOMAC scores, assessing pain, stiffness, and physical function, showed significant improvements for both treatments (Fig. 4). Kim J et al.⁶ reported maximum improvements with ADMSC at 24 months (mean: 29.5), while Çimen et al.² noted notable SVF benefits at 12 months, particularly for pain/+and stiffness. ADMSC demonstrated greater and more sustained improvements in joint function, with superior long-term outcomes at 24 months, whereas SVF effects plateaued after 12 months.

KOOS scores, reflecting knee health, function, and quality of life, highlighted greater efficacy of ADMSC over SVF in three studies⁶,⁸,⁹ (Fig. 4). Yokota et al.⁹ reported significant KOOS improvements with SVF by 24 months (mean improvement: 34.4), indicating long-term benefits. However, Zhang et al.¹⁰ observed slower and less sustained improvements with SVF at 12 and 24 months, suggesting ADMSC offers more pronounced and durable enhancements in knee function and quality of life.

3.4.2 Longevity of pain relief and functional improvement

The analysis of VAS, WOMAC, and KOOS scores showed ADMSC provided superior and sustained improvements in OA management compared to SVF. ADMSC offered prolonged symptom relief, with Kim et al. reporting significant KOOS improvements at 18 and 24 months (p = 0.012). Yokota et al. found 50 % of ADMSC patients achieved MCID on VAS versus 24 % for SVF (p = 0.01) and 43 % on KOOS5 versus 16 % for SVF (p = 0.02). However, differences diminished by 24 months, with no significant VAS or WOMAC distinctions at 6 or 12 months (Kim et al.).

SVF showed early efficacy within the first year but declined over time. Cimen et al. reported symptom improvements at 24 months (p < 0.05), with many patients returning to baseline by 36 months. Rogers et al. noted a plateau in KOOS-Sport and QoL subscales after 12 months, and Zhang et al. reported diminishing effects after one year, though improvements remained significant at 1–3 years (p < 0.05).

Two RCTs established PROMS thresholds. Rogers et al. reported MCID for KOOS subscales exceeded at 12 months before plateauing. Yokota et al. found ADMSC superior to SVF at 12 months, with more patients meeting MCID for VAS (50 % vs. 24 %) and KOOS5 (43 % vs. 16 %) and surpassing PASS for VAS pain (45 % vs. 24 %), though these benefits were not significant at 24 months.

3.4.3 Cartilage thickness assessment and cartilage regeneration

Research on the use of ADMSC and SVF for cartilage regeneration is inconclusive. Out of ten studies, two demonstrated evidence of cartilage regrowth with ADMSC therapy and 4 studies showed no evidence of cartilage regeneration with ADMSC or SVF therapies.

Kim et al. reported significant cartilage regeneration post-ADMSC injection after MOWHTO, with an 81.1 % defect reduction versus 44.4 % in controls and superior MOCART 2.0 scores (76.2 vs. 50.4). Issa et al. found increased cartilage volume 12 months post-ADMSC treatment compared to hyaluronic acid, with MRI showing gains in both knees (+193.36 mm³ and +108.70 mm³) versus reductions in controls. ADMSC also prevented early cartilage deterioration, unlike controls, which showed defect enlargement within six months (35.61 mm², p < 0.05). Kim et al.⁷ and Yokota et al.⁹ found no structural improvements with ADMSC or SVF in MRI or radiographic evaluations up to 24 months. Aletto et al.¹ and Zhang et al.¹⁰ reported no significant cartilage changes with SVF, though it slowed cartilage volume loss over five years compared to controls.

3.4.4 Autologous anti-inflammatory activities

The anti-inflammatory efficacy of ADMSC and SVF in KOA was analysed across seven studies, highlighting the correlation between cytokine modulation and clinical outcomes. Both therapies demonstrated significant potential to alleviate inflammation, stabilize OA progression, and enhance joint function through paracrine signalling. Two meta-analyses and an RCT confirmed ADMSC's ability to stabilize OA via growth factor release and paracrine effects.⁴,⁵,⁶ Issa et al.⁴ reported substantial improvements in OA pain stabilization, with WOMAC scores improving from 45.2 to 28.6 (p < 0.01). ADMSC therapy mitigates chronic inflammation by suppressing T-cell proliferation, inhibiting monocyte maturation, and facilitating anti-inflammatory cytokine release, such as IL-10 and anabolic cytokines.⁶ Jeyaraman et al.⁵ emphasized ECM stabilization and cartilage regeneration, attributing these effects to immunomodulation mechanisms.

Additionally, SVF's rapid anti-inflammatory effects are mediated by bioactive molecules, including interleukins (IL-1Ra, IL-4, IL-10, TGF-β), prostaglandins, and TSG-6, with CD11b-expressing macrophages playing a critical role.³,⁷,¹⁰ Aletto et al.¹ reported significant reductions in pro-inflammatory cytokines—IL-1β by 32.26 %, IL-6 by 58.25 %, and IL-8 by 36.77 %—accompanied by a 70.8 % increase in IL-10 (p < 0.05). Goncharov et al.³ highlighted reductions in oedema and tissue swelling, while Rogers et al.⁸ described the polarization of macrophages to the M2 anti-inflammatory phenotype (expressing IL-4, IL-10, and IGF-1) and the inhibition of TNF-α, contributing to matrix metalloproteinase downregulation. While both therapies share similar paracrine mechanisms, SVF provides immediate symptom relief due to rapid IL-1Ra release, while ADMSC offers more sustained effects through anabolic and immunomodulatory cytokine production. ADMSC's slower onset may be offset by its longer-lasting benefits in stabilizing OA and promoting cartilage repair.⁴,⁷,⁹ These mechanisms highlight the bioactivities favouring long-term joint stability of ADMSC and excelling in rapid symptom alleviation of SVF.

4.2.1 Longevity of pain relief

The immunomodulatory mechanisms of ADMSCs and SVF underpin their analgesic and reparative properties in osteoarthritis.⁷,⁹,³⁰ SVF's rapid release of IL-1Ra and prostaglandins facilitates acute pain relief but peaks by 6 months, requiring further interventions to sustain benefits.¹,³ ADMSC therapy, with its consistent growth factor and cytokine release, extends therapeutic benefits beyond 24 months. Furthermore, ADMSCs regenerate cartilage and restore joint architecture, enhancing biomechanical stability, delaying degenerative progression, and reducing reliance on surgical interventions like total knee replacement. Regenerated cartilage serves to re-establish the articular surface, providing cushioning that minimizes bone-on-bone contact and mechanical irritation, thereby improving overall joint function. This positions ADMSC therapy as a transformative approach to sustainable osteoarthritis care.⁶,⁷

4.2.2 Evidence from PROMS

At 12 months, SVF therapy achieved significant short-term pain reduction, with a mean VAS improvement of 18.10 points,⁸ compared to 16.92 points for ADMSC-treated patients.⁹ However, ADMSC demonstrated greater durability, maintaining efficacy over 24 months, while SVF required reinjections to sustain benefits.⁷

WOMAC scores reflected similar trends, with ADMSC recipients achieving sustained functional improvements, peaking at a mean of 29.5 points at 24 months.⁶ In contrast, SVF benefits plateaued after 12 months without reinjections.²

KOOS outcomes further supported ADMSC's durability, with SVF yielding a mean improvement of 34.4 points at 24 months but with less consistency.⁹ ADMSC patients exhibited stable, pronounced improvements across KOOS dimensions.⁶

Subgroup analyses reinforced ADMSC's sustained efficacy, with 50 % of patients achieving the MCID for pain relief (14 mm VAS) by 12 months compared to 24 % for SVF.⁹ Similarly, 43 % of ADMSC recipients met the KOOS5 MCID (10 points), versus 16 % of SVF-treated patients,⁹ highlighting ADMSC's superior long-term outcomes.

4.2.3 Patient safety & post-operation recovery time

Both ADMSC and SVF therapies demonstrate favourable safety profiles, with adverse events typically mild, self-limiting, and resolving without significant intervention. Most patients resume normal activities within seven days post-injection.³,⁴,⁷ SVF's simplified preparation and immediate availability enhance safety by avoiding rehospitalization and risks associated with ADMSC cell expansion,³ making it suitable for older patients who may not tolerate invasive procedures.¹,⁹ While SVF allows faster recovery and minimizes short-term disruption, it may necessitate repeated treatments, potentially impacting long-term productivity.¹,⁷,¹⁴,¹⁵ Conversely, ADMSC therapy, despite requiring multiple visits, provides prolonged symptom relief, reducing intervention frequency and lifestyle disruption.¹,⁵ Treatment should be tailored to individual factors such as age, disease severity, and functional goals to optimize safety, efficacy, and lifestyle outcomes.

4.2.4 Disease modification

ADMSCs show promise for cartilage regeneration, though results remain inconsistent. Kim et al.⁶ reported a 35.61 mm² reduction in cartilage defect size within six months of ADMSC treatment, compared to no significant change in the SVF group. MRI findings by Issa et al.⁴ demonstrated significant cartilage volume increases in ADMSC-treated knees (left: 193.36 ± 282.80 mm³, right: 108.70 ± 220.13 mm³) versus cartilage volume reductions in hyaluronic acid-treated controls. However, ADMSC therapy often includes adjunctive interventions like MOWHTO to enhance outcomes, complicating the evaluation of its standalone efficacy. Some studies even utilised allogeneic ADMSCs to improve therapeutic effects.⁵ Conversely, SVF consistently showed limited regenerative capacity. Kim et al.,⁷ Yokota et al.,⁹ Aletto et al.,¹ and Zhang et al.¹⁰ found SVF offered minimal cartilage recovery and primarily slowed degeneration.¹⁵,¹⁶ These findings suggest ADMSCs are more promising for cartilage repair and volume retention but fail to provide definitive long-term structural recovery. Standardized protocols, extended follow-ups, and larger trials are essential to thoroughly evaluate the regenerative potential of these therapies, particularly given SVF's limited cartilage regeneration.

4.3.1 Age

Age significantly affects therapy selection and efficacy. ADMSCs, with their homogeneity and high chondrogenic potential, are optimal for younger patients (mean age 51–62 years) with early-stage KOA, offering disease-modifying benefits by preserving cartilage and slowing progression.¹,⁵,³⁴ Younger patients show higher expression of chondrogenic proteins, better cell viability, and antioxidant defences compared to older individuals²²,²³. Conversely, SVF therapy, with its rapid deployment and paracrine effects, is more suited for older patients (>60 years) with advanced KOA, addressing degenerative and inflammatory processes for immediate pain relief.⁵,⁷,⁹ Despite reduced ADMSC function with age, SVF retains efficacy due to its cytokine secretion and heterogeneity, making it practical for older populations.³,²¹

4.3.2 BMI

BMI remarkably impacts regenerative therapy outcomes. ADMSC studies typically involve patients with BMIs between 24.3 and 31.0 kg/m², while SVF trials include more obese patients (BMI >30 kg/m²).² Obesity impairs ADMSC regenerative capacity by promoting a pro-inflammatory phenotype and oxidative stress, reducing therapeutic efficacy²⁴,²⁵. SVF, however, is more effective in obese patients due to higher cell yield from adipose tissue and its anti-inflammatory and paracrine effects, mitigating inflammation and enhancing extracellular matrix regeneration¹,³,⁹,²⁹. These advantages make SVF ideal for advanced KOA in obese individuals needing rapid symptom relief.⁷

4.3.3 Sex differences

Despite the notably impact of sex on KOA progression, current studies lack sufficient data on sex-specific responses to ADMSC and SVF therapies. Female participants dominate KOA studies, reflecting higher prevalence post-menopause due to hormonal changes, biomechanical differences, and thinner cartilage, which increase joint stress and degeneration¹⁸,¹⁹. This highlights a critical gap in understanding sex-based therapeutic outcomes.

4.3.4 Socio-economic factors

Socio-economic aspects, including cost, governance, safety, and logistics, remain underexplored in the literature, therefore limited the applicability and sustainability.¹,³