The composition of cell-based therapies obtained from point-of-care devices/systems which mechanically dissociate lipoaspirate: a scoping review of the literature
Journal of Experimental Orthopaedics volume 9, Article number: 103 (2022)
Cell-based therapies using lipoaspirate are gaining popularity in orthopaedics due to their hypothesised regenerative potential. Several ‘point-of-care’ lipoaspirate-processing devices/systems have become available to isolate cells for therapeutic use, with published evidence reporting their clinical relevance. However, few studies have analysed the composition of their ‘minimally-manipulated’ cellular products in parallel, information that is vital to understand the mechanisms by which these therapies may be efficacious. This scoping review aimed to identify devices/systems using mechanical-only processing of lipoaspirate, the constituents of their cell-based therapies and where available, clinical outcomes.
PRISMA extension for scoping reviews guidelines were followed. MEDLINE, Embase and PubMed databases were systematically searched to identify relevant articles until 21st April 2022. Information relating to cellular composition and clinical outcomes for devices/systems was extracted. Further information was also obtained by individually searching the devices/systems in the PubMed database, Google search engine and contacting manufacturers.
2895 studies were screened and a total of 15 articles (11 = Level 5 evidence) fulfilled the inclusion criteria. 13 unique devices/systems were identified from included studies. All the studies reported cell concentration (cell number regardless of phenotype per millilitre of lipoaspirate) for their devices/systems (range 0.005–21 × 106). Ten reported cell viability (the measure of live cells- range 60–98%), 11 performed immuno-phenotypic analysis of the cell-subtypes and four investigated clinical outcomes of their cellular products. Only two studies reported all four of these parameters.
When focussing on cell concentration, cell viability and MSC immuno-phenotypic analysis alone, the most effective manual devices/systems were ones using filtration and cutting/mincing. However, it was unclear whether high performance in these categories would translate to improved clinical outcomes. Due to the lack of standardisation and heterogeneity of the data, it was also not possible to draw any reliable conclusions and determine the role of these devices/systems in clinical practice at present.
Level of Evidence
Level V Therapeutic.
The underlying principle of cell-based therapy is the targeted delivery of donor cells to achieve a medicinal benefit  and this has been long established in applications like bone marrow transplantation. There is now growing interest in orthopaedics as to whether cell-based therapies can be used to treat diseases such as osteoarthritis (OA), in the hope that they can repair damaged tissue and reduce the need for surgical intervention . Mesenchymal stem cells (MSCs) are found in many locations around the body such as bone marrow and adipose tissue , with those from the latter termed adipose-derived stem cells (ASCs) .
Initially, it was believed that MSCs were the mediators of tissue repair because of their pluripotent ability to differentiate into cartilage and bone tissue . However, due to an inability to control for differentiation in vivo, new evidence suggests that MSCs (when isolated) behave as pericytes and exert their regenerative effects through paracrine or immunogenic ways , rather than cell differentiation. It has therefore been suggested that the acronym ‘MSC’ be changed to ‘medicinal signalling cells’ accordingly .
Small ASC numbers can be isolated in the cellular concoctions of mechanically dissociated and/or enzymatically digested lipoaspirate. Other cell-types present include fibroblasts, immune cells, epithelial cells and endothelial cells . ASCs can be cultured to increase/expand their numbers , but this is time-consuming and unsuitable for point-of-care (POC) treatment . Expansion also involves extensive cell manipulation, and it is unclear whether their properties can be preserved between culture and re-injection [5, 30, 53]. Therefore, using freshly processed lipoaspirate (containing heterogenous cells and not just ASCs) has become more popular  (Fig. 1). Although higher cell numbers are generated with enzyme digestion , these processes can alter cell architecture , so mechanical-only methods have now been favoured for this purpose.
These mechanical methods involve processes like centrifugation, filtration, cutting/mincing, decantation and washing. The inconvenience of needing various equipment at each stage has led to an increasing number of devices or systems that have been developed as ‘all-in-one’ options for easier therapeutic delivery . Although studies have reported clinical benefit from using these devices/systems, little is known about the composition of their cell-based therapies and what is being reinjected into patients [4, 52]- information needed to help us understand how these therapies work. Therefore, the aim of this literature review was to summarise the available mechanical lipoaspirate-processing devices/systems and what they produce. Where available, the composition of their cellular products and clinical outcome data were compared in parallel.
This study was in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis extension for scoping reviews (PRISMA-ScR) guidelines  and was registered on the PROSPERO’s international prospective register of systematic reviews [CRD42021282041]. The five-stage scoping review process described by Arksey and O’Malley  was followed and adaptations from the Joanna Briggs Institute  were incorporated.
Stage 1: Identifying the research question
A preliminary review of the literature showed that:
1) There was a paucity of information about these POC devices/systems.
2) Although clinical outcomes had been reported from using their cell-based therapies, it was unclear what was being reinjected into patients.
This led to the following research question being devised “What do these cell-based therapies contain?” (When using POC devices/systems which mechanically dissociate lipoaspirate).
Stage 2: Identifying the relevant studies
MEDLINE and Embase databases were searched via the Healthcare Database Advanced Search (HDAS) engine from inception to date 1st September 2021. A supplemental search of the native PubMed database was performed as well. A search syntax was formulated (Supplementary material- AdditionalFile1.docx) which focussed on four domains- cell type, adipose tissue, cell isolation and device/system.
Medical Subject Heading (MeSH)-terms and keywords were used to identify relevant articles. The searches were re-run on 21st April 2022 in the Ovid search engine to capture any additional studies. All efforts were made to search the gray literature for relevant articles missed, including a manual search of the references of the included studies and relevant review articles.
Stage 3: Study selection
After deduplication, two reviewers (PL, BG) independently screened the titles and abstracts for relevance. Following this, the full texts of the remaining articles were assessed for eligibility (Table 1). A third senior reviewer (VA) was consulted in the event of a disagreement about a study’s inclusion.
Outcome Measures (definitions):
Cell concentration- Number of cells (irrespective of phenotype) per millilitre of processed lipoaspirate.
Cell yield-Overall number of cells (irrespective of phenotype) that are present in the final product.
Cell viability-A measure of the proportion of cells that are live and healthy .
Cell phenotype- Hallmark characteristics of a cell and its surface markers.
To provide more information about the devices/systems captured in the included studies, an additional search of each device/system was performed in the PubMed database and Google search engine.
Stage 4: Charting the data
The separate search of each device/system was used to ascertain their individual characteristics and use in clinical applications (Table 5). The manufacturer website for each was also analysed for relevant information and peer-reviewed literature. Where possible, companies were contacted by email for any additional articles.
Stage 5: Collating, summarising, and reporting the results
Due to heterogeneity of the data, a formal meta-analysis could not be performed. A narrative analysis of the POC devices/systems, the composition of their therapies, and clinical outcomes (where available) was conducted.
The Oxford Centre for Evidence-Based Medicine (OCEBM) checklist  for therapeutic studies was used to assess the level of evidence of the included studies. Quality review of the studies was performed using a modified ‘Minimum Information for Studies Evaluating Biologics in Orthopaedics (MIBO)’ checklist presented by Murray et al. , which has been designed specifically for MSC-related studies. Adaptations from the STROBE assessment tool  were incorporated for assessing study design. A ‘heat map’ of reporting was subsequently generated (Fig. 3). The tool was validated by the same two reviewers (PL and BG) independently analysing the various domains.
From the primary search 11 studies fulfilled the inclusion criteria. Four additional studies were identified through other means (n = 3 through references, n = 1 additional search), leaving a total of 15 studies for qualitative synthesis (Fig. 2) . Emailing the manufacturers for additional information resulted in five responses (BSLrest- Adinizer, Harvest Technologies Corp- Adiprep + SmartPrep, Tulip Medical- Tulip Nanotransfer, Cytori Therapeutics- Puregraft and Fidia Farmaceutici S.p.A- Hy-Tissue SVF). No new articles for inclusion were identified by these means, but some were used to populate Table 5.
Level of evidence
Most of the included studies were low level evidence (Table 2) [12, 16,17,18, 20, 24, 27, 29, 42, 61, 63, 65, 66, 75, 77] 11 were Level 5 [12, 16, 17, 20, 27, 42, 61, 63, 66, 75, 77] (descriptive laboratory studies), one was Level 4  and only three were Level 2 [24, 29, 65].
Quality Assessment (Fig. 3)
All included studies [12, 16,17,18, 20, 24, 27, 29, 42, 61, 63, 65, 66, 75, 77] disclosed whether they had any financial or other competing interests. 73.3% (n = 11/15 [12, 17, 20, 24, 27, 29, 42, 61, 63, 66, 77]) gave a clear objective which reduced the risk of outcome bias. 26.6% (n = 4/15 [17, 18, 27, 77]) lacked an adequate control group which may have resulted in interpretation bias or publication bias. Most red fields in the heat map were for the ‘Donor details’ and ‘Tissue harvesting’ domains. Notably, only one study  reported donor co-morbidities, one  reported the media for tissue storage following harvest, and one  the time between tissue harvest and processing.
All studies reported a concentration for freshly isolated cells following harvest and device/system administration (Table 3). There were varying definitions for these heterogenous minimally manipulated cells, the most common term that was used was ‘SVF cells’ (n = 9) (Table 4).
Dai Pre et al.  reported the highest concentration achievable (21 ± 0.16 × 106per ml/ lipoaspirate) using the device/system Rigenera. For all devices/systems, mean concentration was 2.30 × 106/ml overall ± 4.92 × 106 (standard deviation). The next highest concentrations were Sese et al.  (6.63 ± 0.47 × 106/ml- Tulip Nanotransfer), Morselli et al.  (2.4 × 106/ml- Lull pgm) and Cohen et al.  (2.24 × 106/ml and 1.44 × 106/ml- Lipocube Nano & Tulip Nanotransfer) accordingly.
Only two thirds of the studies (n = 10) [16,17,18, 27, 29, 61, 63, 65, 66, 77] gave a cellular viability in conjunction with their concentration (Table 3), the highest being Gentile et al.  with 98% using Fastem and Mystem. However, this viability figure was quoted for both devices overall rather than a specific one for each of the device’s products. The next highest figure was 97.55% for Tiryaki et al.  using Lipocube SVF.
For devices/systems with an associated viability figure, mean viability was 80.2% ± 14.0% (standard deviation). The study with the highest cell number with a viability over 90% was Cohen et al.  using Lipocube Nano and Tulip Nanotransfer (Fig. 4).
Ten studies [12, 16,17,18, 20, 24, 27, 65, 66, 75] used flow cytometry analysis to immuno-phenotype the cell subtypes, whereas one  opted for direct immunofluorescence (Table 4). Positive mesenchymal stem cell markers of CD73, CD90 and CD105 (as specified by the ISCT- International Society for Cellular Therapy ), as well as CD44 and CD146 (also found in pericytes ) were reported at varying degrees across all studies. Six studies [12, 16, 17, 27, 65, 66] reported percentages for at least one of these markers in their population of cells following device/system use.
The devices/systems with the highest percentages of MSC CD markers following minimal manipulation were Adiprep- Dragoo et al.  (CD73 60.4%, CD90 65.2%, CD105 33.4%), Lipocube Nano- Cohen et al.  (CD73 53%, CD90 55.8%) and Tulip Nanotransfer- Cohen et al.  (CD73 50%, CD90 42.1%).
Six studies [12, 16, 20, 24, 63, 66] performed immunophenotypic analysis on a control method as well (either enzymatic or mechanical); two [24, 63] for mechanical, with a large difference only observed with Fastem . Three studies [12, 16, 27] performed analysis of the MSC phenotype following culture and consistently achieved above 90% for CD markers 73,90,105.
Devices/systems and their individual characteristics
Out of the 15 studies, 13 unique mechanical devices and systems were identified (Table 5). Five were manufactured by companies in the USA and four in Italy. Traditionally, the mechanical processes used have been centred around three main techniques: decantation, centrifugation and filtration . More novel methods have now been introduced including the physical disruption of tissue, washing and cutting. The most popular techniques adopted were filtration (n = 10), washing (n = 5) and cutting/ mincing (n = 5).
Only four of the included studies [18, 24, 29, 65] assessed clinical outcomes following the use of their device/systems (Table 2). Copcu , Domenis  and Gentile  reported positive outcomes following contouring procedures. Tarallo  reported wound healing improvement using MyStem EVO.
Other clinical applications have been highlighted in Table 5 [7, 15, 21, 22, 33,34,35,36,37,38,39, 47, 51, 54, 55, 57,58,59, 62, 67, 71,72,73, 76]. None of the authors reported the constituents of the cellular therapies used in these studies. Lipogems [7, 21, 36, 47, 57,58,59, 72, 73, 76], MyStem EVO  and Hy-Tissue SVF  were the only device/systems to have been used in orthopaedic application.
This scoping review identified 13 unique mechanical devices/systems from 15 articles that fulfilled the inclusion criteria. The mean cell concentration (cell number generated per millilitre of processed lipoaspirate) from these devices/systems was 2.30 × 106/ml of lipoaspirate (Table 3). Ten of 15 studies gave a cellular viability in conjunction with their concentration (mean 80.2%). 11 studies performed immuno-phenotypic analysis to characterise cell-types (Table 4), with six reporting markers for MSCs. Four studies assessed clinical outcomes. Only two studies [18, 65] reported all four parameters.
The mean cell concentration (2.30 × 106/ml) was higher than concentrations obtained by conventional mechanical methods not using a POC device/system, as shown by Aronowitz et al.  (0.01–0.24 × 106). It is possible that concentrations are greater following device/system use because of reduced handling and processing times. Nonetheless, this figure was skewed by one study  which did not report cell viability.
Viability is the proportion of live and metabolically active cells in the sample, so POC devices/systems should aspire for a cell viability as close to 100% as possible. The International Federation for Adipose Therapeutics and Science (IFATS) has since proposed a minimum threshold of 70%  for cells, but this was to allow for good cell expansion. Only nine devices/systems (seven studies) reported a cell viability above 70% [16,17,18, 29, 61, 65, 66]. Of these, the mean cell concentration was 1.55 × 106 (0.005–6.63 × 106). This was still higher than that of previously published literature , which indicates the therapeutic promise that these POC devices/systems may present.
However, this places significant weight on cell concentration as a variable. The cell yield (total number of cells delivered to the patient) is affected by the volume of the final product, as well as cell concentration. This varies across studies (Table 3) and depends on the therapeutic indication that is required. Additionally, evidence for a correlation between cell number and observed clinical benefit is inconclusive at present . Theoretically, higher cell concentrations should result in higher ASC numbers (when accounting for the final volume of product) and therefore better outcomes, but this hypothesis is making the assumption that ASCs are the critical cell type in achieving clinical benefit. If so, the most effective devices/systems were the Tulip Nanotransfer which isolated 6.63 × 106 cells/ml at 76.8% viability and Lipocube Nano- 2.24 × 106 cells/ml at 96.05% viability; the highest concentrations and viability combined (Fig. 3). These devices/systems utilise filtration and cutting/mincing in their processing, and avoid other steps such as centrifugation, sedimentation and washing, hence the terms microfragmented adipose tissue (MFAT) or nanofat  being used in the literature to describe the processed lipoaspirate.
On the other hand, there was variability in the concentrations obtained from these devices/systems [17, 61] and others across different studies. Therefore, it is unclear whether the higher concentrations obtained overall were significant or erroneous. It is likely that such variation was due to the lack of standardisation in the preparation methods and laboratory analysis (Table 3). Variability was also observed intra study with Dai Pre et al.  demonstrating that harvesting site could affect cell concentration. In this study, it appeared that lipoaspiration from the thigh resulted in higher cell numbers than the abdomen . This is a key observation when considering the different donor sites across our studies (Table 3). However, more work is required to confirm these findings and establish the best location. Publications have shown other influential factors to be patient demographics , harvesting technique [2, 41] and volume processed . The reporting of these factors is variable and has been highlighted in the quality review of studies (Fig. 3). Such non-reproducible results affect the reliability of the concentrations and the subsequent conclusions that can be drawn.
In addition to cell concentration and viability, six studies undertook MSC surface marker analysis to confirm the presence of ASCs within the therapies obtained [12, 16, 17, 27, 65, 66]. The Adiprep system  had the highest proportion of MSC CD markers (CD73 60.4%, CD90 65.2%, CD105 33.4%), with Lipocube Nano and Tulip Nanotransfer second and third  (CD73 53%, CD90 55.8% and CD73 50%, CD90 42.2% respectively). Despite these results, these studies did not have suitable control methods for comparison (Table 4). Again, these markers only hold particular importance if ASCs are the therapeutic cell type. New information suggests that the other cells within the niche, including: preadipocytes, endothelial cells, macrophages and T-Cells [9, 11], may be just as important (as the ASCs/MSCs act in a paracrine manner). Reporting of these cell subtypes other than just MSCs alone would help us understand the basic science better.
Although these studies have focussed on the cells generated, other authors have highlighted the regenerative capabilities of the cell-free components in processed lipoaspirate. Sarkanen et al.  showed that adipogenesis could be induced by using cell-free extract of adipose tissue, possibly due to extracellular vesicles (membrane-bound phospholipids found in the lipoaspirate fluid) . Other factors that could be important include: lipids, RNA, miRNA, DNA, soluble factors and other signalling molecules and proteins, all of which play a role in regulating biological behaviour and immunomodulation . Consideration of using protein assays and other focussed analytical techniques in future studies for these molecules would be useful.
We are still at a juvenile stage in understanding the basic science for these minimally manipulated products, especially given the cellular heterogeneity, small number of ASCs and extracellular components involved. Therefore, improved reporting of their composition is needed so that we can correlate the cellular and molecular components that are present in these therapies with clinical gain [49, 52]. As this review highlights, there is a paucity of studies (four [18, 24, 29, 65]) that have reported not only cellular composition data adequately, but corresponding clinical outcomes as well. Interestingly, these studies were for cosmetic purposes only. The trophic properties of uncultured cells from processed lipoaspirates have been well reported , so the use of these POC devices/systems in the aesthetic industry has gained particular traction.
Other publications have reported clinical outcome data alone from using these POC devices/systems (Table 5), but only Lipogems [7, 21, 36, 47, 57,58,59, 72, 73, 76], MyStem EVO  and Hy-Tissue SVF  been used in orthopaedic related studies. Lipogems is a closed system which performs washing, filtration and sedimentation, with manual shaking and emulsification also required . It has become popular in orthopaedics, having established an early patent for clinical use , as well as being a user-friendly system . Furthermore, its marketing has generated commercial interest amongst consumers. However, as with any marketing, there is the potential for dissemination of false or overexaggerated claims, leading to misunderstanding amongst clinicians . This can hinder further progress within the field. As this review has established, it is not clear what is being reinjected into patients when using these therapies, so it is important that clinicians are made aware of this for their clinical practice.
A weakness of this review is the lack of standardisation in the preparation methods and analytical techniques used across the studies. A systematic review by Robinson et al. , which analysed the application of MSCs in orthopaedics and sports medicine, similarly highlighted the inadequate reporting of preparation methods and composition. Standardisation of protocols to allow for fairer comparisons between studies would be helpful. Both the ‘DOSES’ tool  and ‘MIBO’ checklist  described by Murray et al. were expert consensuses for improving the transparency of cell-based therapy reporting and should be considered in all studies within the field. Another weakness is that some publications may not have been captured if the device/system name was used in the abstract instead of generic search terms (‘device’ or ‘system’). Further studies may have also been missed if they were either unpublished or in non-peer reviewed journals.
This review increases awareness of POC devices/systems so that users can make informed decisions about using their cellular products for treating musculoskeletal conditions. Regarding cell concentration, cell viability and MSC immunophenotypic analysis, the most effective devices/systems were the manual devices/systems utilising filtration and cutting/mincing techniques. However, it was not known whether high performance in these categories would translate to improved clinical outcomes, let alone which components of the product (cellular or non-cellular) influence the clinical results.
Due to the lack of standardisation in preparation methods and analytical techniques, as well as heterogeneity of the data, it was not possible to draw any reliable conclusions and determine the role of these devices/systems in clinical practice at present. Future studies that investigate clinical outcomes from using these POC devices/systems should improve their reporting of cellular and non-cellular composition (to help to understand the basic science better) as well as pursue minimum standard requirements for preparation protocols and laboratory analysis.
Availability of data and materials
All data cited and referenced where applicable.
Mesenchymal stem cells
Adipose-derived stem cells
Total stromal cells
Microfragmented adipose tissue
Stromal vascular fraction
Preferred Reporting Items for Systematic Review and Meta-Analysis extension for scoping reviews
Medical Subject Heading
Randomised control trials
Oxford Centre for Evidence-Based Medicine
Minimum Information for Studies Evaluating Biologics in Orthopaedics
Strengthening the Reporting of Observational studies in Epidemiology
: International Federation for Adipose Therapeutics and Science
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The authors would like to thank Ms Potenza Atiogbe, Multi-professional Education and Library Services Manager at Epsom and St Helier’s NHS Foundation Trust, for her support and help in searching the literature and obtaining some of the full-text articles used in this review.
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Liu, P., Gurung, B., Afzal, I. et al. The composition of cell-based therapies obtained from point-of-care devices/systems which mechanically dissociate lipoaspirate: a scoping review of the literature. J EXP ORTOP 9, 103 (2022). https://doi.org/10.1186/s40634-022-00537-0