Clarifying the critical differences between the enzymatic stromal vascular fraction and the mechanically derived stromal vascular tissue or nanofat for spinal cord injury applications

Abstract

This letter aims to address the increasing confusion surrounding the concepts and terminology of enzymatically derived stromal vascular fraction (eSVF) and mechanically processed adipose tissue, which is often referred to as stromal vascular tissue (mSVT) or nanofat. Although these products are often presented as equivalent, they differ fundamentally in their biological composition, processing methods and regulatory classification. Enzymatic digestion yields a homogeneous, adipocyte-free cellular suspension, whereas mechanical processing preserves adipocytes, extracellular matrix fragments and tissue architecture. In the context of spinal cord injury, these differences give rise to biologically plausible concerns and procedural constraints, particularly with regard to intramedullary delivery. This work highlights the importance of precise terminology, transparent reporting of methods, and careful regulatory alignment to ensure the safe and scientifically sound translation of clinical applications.

Letter:

Dear Editor,

We wish to address the growing conceptual and terminological confusion in the field of adipose-derived cell-based therapies concerning the interchangeable use of two fundamentally distinct biological products: (1) the stromal vascular fraction obtained by enzymatic digestion (eSVF) and (2) the mechanically derived stromal vascular tissue (mSVT), which is commonly referred to as ‘nanofat’. This distinction is not merely semantic: it has significant biological, regulatory and safety implications, particularly in the context of future applications for spinal cord injury (SCI).

Current regulatory frameworks have inadvertently contributed to this confusion. In Europe, enzymatic isolation of SVF using collagenase is considered substantial manipulation and therefore falls under the Advanced Therapy Medicinal Product (ATMP) classification according to Regulation (EC) No 1394/2007. This restrictive framework has encouraged the development of mechanical devices that are marketed as enabling ‘SVF extraction without enzymes’. While these devices often fall outside of ATMP regulation, the biological products they generate do not correspond to the definition of a stromal vascular fraction. Consequently, clinicians and researchers may mistakenly believe that they are working with an SVF-like preparation when, in reality, they are handling mechanically fragmented adipose tissue.

eSVF and mSVF are not equivalent biological entities. Collagenase digestion fully dissociates the extracellular matrix, yielding a homogeneous cellular suspension known as the stromal vascular fraction. This is composed of mesenchymal stromal/stem cells, endothelial and stromal progenitors, and immune cells, with mature adipocytes being effectively eliminated [1]. In contrast, mechanical processing methods, including emulsification using shear forces or micronisation using cutting devices, do not achieve complete matrix dissociation. These approaches generate stromal vascular tissue containing residual mature adipocytes, adipoblasts, pre-adipocytes, micro-fragments of the extracellular matrix and partially preserved vascular and stromal structures. This product closely resembles what is commonly referred to as nanofat [2].

The persistence of adipocytes and adipose matrix components in mSVT is significant and represents a fundamental biological difference from eSVF. Although there is currently a lack of direct experimental evidence demonstrating harm in SCI models, several theoretical and biologically plausible concerns arise. Mature adipocytes undergo hypertrophy, adipoblasts retain proliferative capacity and adipose tissue secretes a wide range of adipokines with complex, context-dependent paracrine effects [3, 4]. In the highly vulnerable intramedullary environment, these properties give rise to concerns about unpredictable biological behavior, including the persistence of ectopic adipose tissue, the promotion of fibrosis and the interference with neuroprotective and neuroregenerative processes.

From a procedural standpoint, the intramedullary administration of mechanically derived stromal vascular tissue gives rise to additional theoretical concerns. Unlike eSVF, which can be concentrated into very small volumes suitable for precise intramedullary delivery, mechanically processed adipose tissue retains a tissue-like structure that may require larger injection volumes. While quantitative thresholds for safe intramedullary injection pressure have yet to be clearly defined, an increased volume or density of tissue could theoretically increase the risk of local tissue distortion or pressure-related injury. These considerations are particularly relevant in SCI, where even minimal secondary injury may have significant functional consequences [5].

It is important to emphasize that mSVT or nanofat may be suitable for other clinical applications, such as wound healing, aesthetic surgery and soft-tissue reconstruction, where the presence of adipocytes may be beneficial or at least not detrimental. However, it is problematic to extrapolate these applications to SCI without acknowledging the profound biological and anatomical differences.

Clear terminology and transparent reporting are therefore urgently needed. We strongly encourage the community to adopt biologically accurate nomenclature that reflects the fundamental differences between these products:

• eSVF should refer exclusively to the stromal vascular fraction obtained through enzymatic digestion;

• mSVT or nanofat should designate mechanically fragmented adipose tissue containing adipocytes and stromal components.

Using the term ‘SVF’ for mechanically derived products is scientifically inaccurate and obscures essential biological and regulatory distinctions.

To improve clarity and reproducibility in future studies, we recommend that publications involving adipose-derived products systematically report the following: (i) the method of tissue processing (enzymatic versus mechanical); (ii) the presence or absence of mature adipocytes; (iii) the final volume and concentration of the injectate; and (iv) the intended anatomical target. Such transparent reporting would enable meaningful comparisons to be made between studies and prevent the inappropriate extrapolation of results across fundamentally different biological products.

Conclusion

Assuming that mechanically derived stromal vascular tissue is equivalent to an enzymatic stromal vascular fraction is scientifically incorrect and may have significant implications for regulatory oversight and patient safety. In the specific context SCI, mSVT appears theoretically unsuitable for intramedullary delivery in terms of both injectable volume constraints and biological behavior. Therefore, it warrants particular caution.

Perspectives

Current European regulations impose particularly restrictive constraints on eSVF, which differ from the regulatory approaches adopted in some non-European jurisdictions. International regulatory landscapes remain heterogeneous, with varying levels of permissiveness and oversight. Continued regulatory dialogue is needed to ensure that patient safety, scientific rigor and clinical innovation are appropriately balanced rather than strategies aimed at circumventing existing frameworks being encouraged. In parallel, manufacturers of mechanical devices would need to substantially enhance the stromal vascular component of mSVT before they can legitimately refer to their product as a mechanical stromal vascular fraction of any kind.

Sincerely,

Dr Caroline NONARATH and Dr Nicolas SERRATRICE.

Author contributions

CN & NS contribute equally to this work.

Funding

No funding.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.