Structural and biological Role of HA
It is well known that hyaluronic acid (HA), particularly at a high molecular weight, is very hydrophilic, and is therefore characterized by excellent skin hydrating capabilities(1). Due to its high affinity for water, HA plays an integral role in maintenance and regulation of the homeostasis of intradermic water. Moreover, it has been demonstrated that HMW HA protects cells and Extra Cellular Matrix (ECM) components from damage by free radicals(2).
Besides playing a relevant role as a structural polymer, HA exerts several biological actions, which may vary according to molecular weight(3). Research shows that at lower molecular weight (around 200kDa), HA is characterized by its bioactivating and reparative properties.
In studies evaluating the effect on proliferative activity in cultures of cutaneous fibroblasts and keratinocytes, 200 kDa HA was reported to induce the strongest proliferative effect on both cell types, compared to non-crosslinked and cross-linked HA of different MW(4).

 
Weight - Concentration – Technology (W.C.T.) Concept
Many different effects of hyaluronan observed in in vitro and in vivo systems depend on its molecular weight(5) and concentration. Furthermore, in order to exert specific biological activities, the HA molecular weight fraction needs to be very «pure» (i.e. not containing HA polymer chains of significantly different length) when administered exogenously. For this reason, the technology with which hyaluronan-based products are developed becomes important as well.

Fidia’s approach in developing the Hyal System Line lies in the Weight - Concentration – Technology (WCT) Concept, that is the unique combination of these three variables exploiting different structural and biological properties of HA, enabling each Hyal System Line product to bring out different targeted benefits.

Unlocking the Regenerative Potential of HA with ACP Technology
The patented Auto-Crosslinked Polymer (ACP) Technology developed by Fidia allows to stabilize the biologically active 200kDa fraction of HA through cross-linking without involving any chemical agent(6). The crosslinked hyaluronan is obtained via formation of covalent ester bonds between hydroxyl and carboxyl groups of the hyaluronan molecule, with no spacers between them. Such ester bonds may be either intramolecular (within a single hyaluronan molecule) or intermolecular (linking two hyaluronan molecules together). The key advantage in the direct formation of ester linkages over alternative methods is that no foreign substances are introduced into the molecule. In this way, catabolism of ACP at tissue level leads to the slow release of unmodified 200KDa hyaluronan, which exerts its biostimulating effect resulting in:
Higher cell density: the 200 kDa HA fraction supports cell proliferation4 to afford increased tissue density(7),
Increased ECM neosynthesis: the 200kDa HA fraction seems to improve the CD44 receptor-mediated(8) neo-formation of matrix components(9),
Rejuvenated skin: the combination of increased tissue hydration, and cell and ECM density results in improved skin elasticity and tone(10).
The biostimulation achieved by 200kDa HA relies clearly on organism response to a natural compound of the extracellular matrix, instead of a reaction to a foreign body. By stimulating the body's natural response, rejuvenation in the deeper layers of the skin is achieved.

When injected into the deep dermis, HYAL SYSTEM ACP significantly improves skin quality, minimizing micro-laxity, fine lines, creases and other visible signs(10). With one treatment cycle, it reduces the appearance of deeper blemishes and wrinkles, resulting in smoother, firmer and more elastic skin and a rejuvenated appearance(11).

In the context of choosing the most effective type of aesthetic treatment to correct the various imperfections of the face, it is impossible to ignore the structural varieties present in it. The choice of interventions to be performed on the face depends not only on knowing the macroscopic anatomy, but also on its microscopic structure. Bi-modal ultrasound examination can be a valuable tool for pre-treatment anatomical assessment. Indeed, by using a high-resolution 24 MHz ultrasound, the analysis of different structures of the face is possible. Prof. Sbarbati from University of Verona and his team used this evaluation method, as well as an elastosonography, in order to evaluate the stiffness properties ofthe different structures of the face in patients injected with HYAL SYSTEM ACP. During Fidia’s symposium they will be presenting the data obtained.

The team of Prof. Sbarbati has also shown the role of hyaluronic acid in promoting MSCs differentiation to adipose cells. Their experiments showed that the extent of differentiation depends on HA physicochemical characteristics since they demonstrated that LMW HA and ACP induced higher adipogenic differentiation compared to HMW HA. These data will also be presented in the symposium.

1. Narurkar VA, Fabi SG, Bucay VW et al. A New Approach in Topical Hyaluronic Acid: Going Beyond Instant Benefits to Restore Epidermal HA Homeostasis. Journal of Drugs in Dermatology. 2016: 15; 1 (Supp. 2)
2. Presti D, Scott JE,  Hyaluronan-mediated protective effect against cell damage caused by enzymatically produced hydroxyl (OH.) radicals is dependent on hyaluronan molecular mass..Cell Biochem Funct. 1994 Dec;12(4):281-8.
3. Cooper CA, Brown KK, Meletis CD, Zabriskie N. Inflammation and hyaluronic acid. Altern Complement Therapies 2008;14:78e84
4. Wohlrab J, Wohlrab D, Neubert RH. Comparison of noncross-linked and cross-linked hyaluronic acid with regard to efficacy of the proliferative activity of cutaneous fibroblasts and keratinocytes in vitro. J Cosmet Dermatol. 2013; 12(1):36-40.
5. J M Cyphert, Size Matters: Molecular Weight Specificity of Hyaluronan Effects in Cell Biology,  International Journal of Cell Biology Volume 2015, Article ID 563818
6. S. Pluda et al. Hyaluronic acid auto-crosslinked polymer (ACP): Reaction monitoring, process investigation and hyaluronidase stability,  Carbohydrate Research 433 (2016) 47e53
7. Alessandrini & Tretyakova, The Rejuvenating Effect and Tolerability of an Auto-Cross- Linked Hyaluronic Acid on Decolletage: A Pilot Prospective Study Aesth Plast Surg (2018) 42:520–529
8. Weigel & Baggenstoss, What is special about 200 kDa hyaluronan that activates hyaluronan receptor signaling? Glycobiology, 2017, vol. 27, no. 9, 868–877
9. Maurizio Ceccarelli & Cristiano Curcio, Biostimulation and Biorestructuration of the Skin, The Physiological medical Letter, Vol. 1, Jan 2010, no 2
10. Hyal System ACP IFU, rev. 11.03.2021
11. Di Pietro et al. Facial wrinkles correction and skin rejuvenation (biostimulation) by auto-crosslinked hyaluronic acid. J Plastic Dermatol 2007;3(2):5-13