Addressing the soft tissue volume loss is an important issue in plastic, reconstructive and aesthetic surgery. Soft tissue augmentation could be needed after a trauma or surgery as well as in ageing. Although in some cases a reconstruction with tissue flaps, a complex procedure, is mandatory, often just filling the subcutaneous tissue with a “volumazaitor” is enough.
Nowadays, besides implants for breast augmentation, the most used techniques for soft tissue augmentation are either autologous fat grafting or injection of synthetic product (e.g.
hyaluronic acid, collagen). Even there is an increase demand for such kind of procedures, none of them are ideal. Main disadvantages of actual synthetic products are their complete resorption after ~6 months for resorbable products such as hyaluronic acid or the high risk of granuloma for “permanent” products like calcium hydroxyapatite. Fat grafting, although its numerous advantages, has a resorption rate of 30 to 80% which is a major issue requiring often multiple surgical procedures. Moreover, some patients do not have enough fat depots to be harvested.
Recently, there is tempting to pharmacologically target one or several steps of triglyceride synthesis to modulate the adipocytes volume and to improve autologous fat grafting survival.
However, since lipids are ubiquitous, a systemic action could have dramatic consequences by forwarding fatty acids to other tissues (e.g. liver, vessels) and triggering lipotoxicity. In addition this may affect the cell signaling and cell’s integrity as lipids play a key role in these processes.
Therefore, a solution that offers the possibility to “nourish” adipocytes in situ, and only in the desired site would be ideal.
For reminder, an adipocyte is fundamentally composed of triglycerides (up to 80-95% of volume) which generally derive from extracellular sources. Lipids enter adipocytes in the form of fatty acids. This transport and intracellular lipid storage, adipogenesis, are orchestrated by different factors such as insulin as detailed in Sect. 2.1.2.13 Taking in account all these phenomenon, and the clinical need for in situ adipocyte augmentation, in collaboration with a start-up (PB&B) and Ecole Polytechnique de Lausanne (EPFL) we are developing an innovative product.
Figure 14 PLGA microspheres produced by a WOW emulsion (Magnification -10 x)
Innovation resides in the sustained delivery of lipids by a biodegradable microparticles. Injecting lipids alone into fat tissue degrade and diffuse rapidly, leading to two main problems: one being a short lived effect and the second being the risk of inducing side effects in an unintended area of the body. The most promising solution to solve these problems is to have a localized depot of these lipids that can be released in a controlled manner.
In our innovation, we aim to use microspheres encapsulating lipids that will be released slowly over a precise period of time. Furthermore to improve adipogenesis locally, lipid absorption by adipocytes and their storage, bioactive molecules known to be adipogenic could be added to these microspheres and be released over time.
The designed product would be composed of 3 main elements:
1) a selection of lipids that are known to increase efficiently adipocyte’s volume (e.g. oleic acid, linoleic acid),
2) biological factors recognized for their lipogenic effect (e.g insulin, FGF) and
3) a biocompatible slow-degradable microspheres made of polylactic-glycolic acid (PLGA) containing lipids and biological factors that they release over time. (see Fig 14)
The final product would be an injectable liquid that physicians can inject, like hyaluronic acid, to patients to enhance soft tissue volume “permanently”. We expect that the volumator effect will last for a long term. As mentioned (Sect. 2.2.2) once adipose tissue reaches a volume, they tend to conserve their volume by an autoregulation system.10,49,50 Moreover, as Spalding et al.
demonstrated, adipocytes have a 10 years live.9 And interestingly this long live is independent of adipocytes size changing.
We performed preliminary in vivo experiments by injecting our microspheres to mice inguinal fat pad. They suggested that the specific microspheres, encapsulating lipids and biological
Figure 15 Sample image depicting the 3D CTscan reconstruction of mice inguinal fat pad (bleu) 15 days after injection of empty PLGA microspheres (left image) and lipid loaded microspheres (right image).
Significantly the loaded microspheres enhance the volume of the inguinal fat pad 15 days compared to empty microspheres.
factors, enhance significantly the inguinal fat pad volume compared to all controls on day 15 and day 30 after injection. (see Fig. 15)
Based on these encouraging results, we obtained a Commission for Technology and Innovation (CTI) funding. The aim of this CTI project is to conduct the pre-clinical trials necessary to initiate clinical trials and bring to market a product for use in plastic, reconstructive and aesthetic procedures.
The overall goals of this project in collaboration with EPFL are: 1) proof of technology in terms of efficacy and durability of the results, 2) producing safety and pharmacokinetic data, 3) optimizing the formulation and 4) establishing concrete protocols for production and quality control of microspheres to be used for clinical testing and scale up in the future.
4 Conclusion
Adipose tissue, formerly decried as the main responsible for metabolic diseases, has acquired an entirely different status of a useful regenerative cells reservoir.
With increasing prevalence of obesity, particularly in children, prevention of the obesity, specifically at the young child is primordial. As the adipocyte hyperplasia during childhood or adult excessive weight gain seems mostly irreversible, this prevention is significantly more efficient than the overweigh treatment.
New knowledge about the adipose tissue behavior and its related comorbidities opens new therapeutic perspectives for weight loss. Anti-inflammatory or lipolysis moderators could be in future the main approaches for adipose-related comorbidities treatment.
Currently for morbid obese patients, the gold standard treatment is bariatric surgery. Besides its efficiency for weight and comorbidities reduction, it provokes often bothering skin excess that has to be corrected by plastic surgery. Unfortunately, this procedure is considered as an
“aesthetic treatment” by health insurance companies that don’t usually reimburse the cost. It is therefore the duty of scientific community, to demonstrate that plastic surgery after massive weight loss is a cost-effective reconstructive surgery. Morbid obesity is a real disease.
Therefore, skin excess should be considered as a sequela of obesity treatment. And the cost of body contouring, considered as the treatment of this sequela, should be covered by health insurance.
On the other hand, adipose tissue gained a significant interest as a promising and cost-effective source of autologous stem cells that can be used for tissue engineering, tissue regeneration or cell therapy.
To make the AT-MSCs culture safer and more efficient for bench-to-bed translation, autologous PRP could substitute all non-autologous culture media that are used at present. As a concentrated source of growth factors and cytokines, PRP is nowadays recognized as a new developing area for clinicians and researchers. Autologous PRP could be applied in the future with safety for
expansion of other cell types than AT-MSCs, such as keratinocytes culture for burns or Langerhans pancreatic cells for diabetics.
The abundance of regenerative cells in adipose tissue raises the possibility to consider adipose tissue as a physiological cell reservoir that can be recruited in the event of an injury or tissue regeneration.
However, the enthusiasm for stem cells therapy has to be moderated by the fact that our current knowledge is limited. Nowadays, we don’t have enough skills to control the multipotency properties of stem cells. The immunosuppressive effects associated with the angiogenic properties of AT-MSCs raise the crucial question of a possible interaction between stem cells and cancer cells. Before to treat any of our patients with “stem cells”, all the scientific steps required to confirm the safety and efficiently of the treatment have to be respected. In vitro and in vivo experiments are essential, and clinical trials primordial.
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