Advances in hyaluronic acid dermal fillers

Advances in hyaluronic acid dermal fillers

Mrs Alexandra Mills Haq and Professor Syed Haq discuss monophasic technology

HA2Hyaluronic acid (HA) is a natural, high molecular weight repetitive disaccharide macromolecule that exhibits no species or organ specificity in its natural form. It is composed of two key subunits; D-glucuronic acid and N-acetyl-D-glycosamine monosaccharides. The average human body contains 15 g of HA, 50% of which is located in the skin (primarily dermal). In its natural form HA is highly soluble, not immunogenic and has a rapid turnover through enzymatic and free radical degradation with a half-life of 24hr in vivo. Immunological tolerance and hygroscopic properties render the HA molecule an excellent candidate for volumising the skin therefore.

The development of stabilised forms of HA dermal fillers has expanded exponentially over the past decade, with cross-linking technology providing an important bridge in aesthetic medicine for non-permanent facial augmentation. Cross-linking HA macromolecules by intermolecular bonds stabilise the superstructure, which would otherwise be a linear macromolecule. The Avian derived form of HA filler, synthesised from rooster combs are less commonly used now due to allergic reactions and increased sensitisation from repetitive use. Many current HA fillers are derived from streptococcus or staphylococcus equine bacterium biofermentation using the cross-linking binding agent, 1,4-butanediol diglycidyl ether. The principal reason behind this is due to the higher purity, reduced immunogenicity, viscosity and non-animal origin.


HA dermal fillers can be classified into two main groups: cohesive (monophasic) or non-cohesive (biphasic—NASHA technology [Restylane]) depending on the method of development. The cohesive (monophasic) fillers are composed of a single phase of HA, which may be cross-linked once as seen with the monodensified form [Juvederm]) or continuously as with the polydensified series [Belotero]). The cohesive monodensified filler is characterised by a highly cross-linked smooth gel that results from homogenisation of the manufacturing process. A series of the cohesive polydensified fillers importantly are currently manufactured in combination with Cohesive Polydensified Matrix (CPM) technology which is characterised by variable densities of cross-linked HA zones. This ensures optimal spreading of the gel into surrounding tissue allowing larger spaces to be filled with denser parts of the gel and finer pericellular tissue spaces to retain low-density gel.

Monophasic vs biphasic

One of the increasing trends seen in the production of HA fillers is in the use of higher concentrations of HA which equates to a longer duration in situ. The general consensus is that 20mg/g of HA is considered to be the optimal concentration in dermal fillers though HA dermal fillers with higher concentrations are currently being used in a monophase.

Importantly some manufacturers have described the monophasic versus biphasic debate as “semantics”. It is true that all HA gel fillers are monophasic when in a syringe in vitro, however they are not when placed in an in vivo environment. Particle size does matter, uniformity of size can be an advantage but also a disadvantage as uniformity on a macroscopic level in the dermis of the skin does not exist, so variation in size could provide a biological and clinical advantage under certain circumstances and certain anatomical considerations are taken into account, though this question needs further investigation.


An example of a comparative analysis was exemplified by the elucidation of the cellular behaviour of HA fillers in vivo in human skin samples by Tran et al. 2014 using monophasic versus biphasic fillers. Histological analysis of the skin samples harvested from points overlying the iliac crest were used from 15 subjects and taken at 8 and 114 days. These samples demonstrated that the tested HA fillers showed specific characteristic biointegration patterns in the reticular dermis. Observations under the optical and electron microscopes revealed morphological conservation of cutaneous structures. Immuno-histochemical results confirmed absence of inflammation, immune response and granuloma. The monophasic and biphasic dermal fillers show an excellent tolerability and preservation of the dermal cells and matrix components. Their tissue integration was dependent on their visco-elastic properties. Interestingly, Tran et al., 2014 concluded that the cohesive polydensified filler when investigated showed the most homogeneous integration with an optimal spreading within the reticular dermis, which was achieved by filling even the smallest spaces between collagen bundles and elastin fibrils, while preserving the structural integrity of the latter. Of note comparable clinical efficacy was observed in this study together with one conducted by Buntrock et al., 2013 who found that irrespective of whether the dermal filler was monophasic or biphasic in nature, the resulting clinical readout was comparable as defined by an analysis of the wrinkle severity rating scale at 2, 4 and 48 weeks in patients treated with a single injection into the naso-labial fold.


Further advances have taken place in dermal filler monophasic HA technology with the introduction of non-particulate, non-CPM based derivatives. TEOXANE Laboratories of Geneva, Switzerland currently use a new range of monophasic non-animal based HA product. Two formulae exist – TEOSYAL  27 G and 30 G—each with monophasic cross-linked hyaluronic acid macromolecules—25 mg/ml. The primary characteristic is that the HA is formed as a strong ribbon using a patented manufacturing protocol (Figure 1) which does not create any particulate matter, this provides high viscosity and elasticity properties (which creates a less elastic (lower G’—elastic modulus) and highly cohesive filler (high cohesive index) with resistance to degradation and migration. The product in vivo lasts between six to nine months. In a study by Nast et al., 2011, a split face trial with correction of moderate to sever nasolabial folds using either the Teoxane monophasic versus a commonly used biphasic filler showed that in general comparable results were observed, though there was a trend in the double-blind randomised controlled trial which favoured the monophasic filler in terms of wrinkle severity rating scale, global aesthetic improvement scale and a reduced volume requirement for reinjection correction.


TEOXANE have gone further with their scientific development by creating a universally unique formulation that combines high concentrations of free HA (15mg/g) integrated with a patented Dermo-Restructuring Complex (Figure 2). The net effect of this is to create of what I term a s a “gain of function” dermal filler that maximises spreading potential in the midst of tackling dermal deep rehydration and redensification. The TEOSYAL. PureSense Redensity Dermo-Restructuring Complex combines natural components involved in redensifying the dermis and providing antioxidant protection from three potent antioxidants, two minerals, one vitamin and eight amino acids. The Patented Dermo-Restructuring Complex fortified the restructuration of the dermis with cellular regeneration as defined by increased collagen IV and fibrillin-1. The improved cutaneous hydration was due to 15x fold increase in acidic GAGs deposition in the epidermis with an overall reduction in photo-oxidant damage.

Particulate vs non-particulate

What of the question particulate versus non-particulate? Are they all created equal. In essence the answer is no with the key difference between particulate and non-particulate HA fillers based on newer technological advances with non-particulate (gel) fillers claiming that they are either multi-cross-linked, double cross-linked or monophasic. In reality the gels are single cross-linked with an ether bond in a two stage manufacturing process; with the first stage creating BDDE cross-links between HA long chains, and the second stage involving bonds between shorter HA chains.

Clinical consideration

The sum effect of intrinsic ageing and long-term environmental exposure to ultraviolet and infrared radiation, together with pollution, and the underlying individuals genetic makeup define the severity and rate of development of wrinkles in our skin over time. Characteristic changes develop that reflect the level at which the anatomical layers within our skin and subcutaneous tissue become damaged. Macro-pathological features such punctate dyschromia, diffuse hyperpigmentation, tissue atrophy, telangiectasia, skin laxity and rhytides are examples of such changes.

Much emphasis has been place upon gaining an increasingly youthful and refreshed appearance through the use of facial rejuvenation treatments with practitioners often neglecting an area that has been dogged by ineffective and/or short-term methods of addressing the skin around the neck and chest (décolletage) areas. Patients are increasingly aware of the transition between the look that they are able to achieve in their face, which often starkly contrasts what they see in the summer months over their chest and neck areas. These changes highlight photo-ageing of the décolletage, resulting in frequent requests for cosmetic enhancement of the said areas.

Multiple modalities can be used either as a stand alone or combined treatment for the rejuvenation of the décolletage, from injectables, neurotoxins, chemical peels, sclerotherapy, photodynamic therapy, intense pulsed light, micro-focused ultrasound with visualisation, q-switched lasers, non-ablative fractionated lasers, and ablative fractionated lasers.

The use of wrinkle scales in aesthetic medicine has allowed the field to better evaluate patients and determine treatment outcomes through objective and standardised methods of assessment. The Fabi-Bolton (F-B) chest wrinkle scale for example was developed as a 5-point scale photo-numeric wrinkle assessment scale using standardised photographic methodology to obtain reference photographs that grades chest wrinkle severity from grade 1 to grade 5. The full spectrum of chest wrinkle severity were accordingly selected when creating the scale and classified as follows: 5-point wrinkle scale (1 = wrinkles absent; 2 = shallow but visible wrinkles; 3 = moderately deep wrinkles; 4 = deep wrinkles, with well-defined edges; 5 = wrinkles very deep with redundant folds).

The F-B chest wrinkle scale can be used as a simple clinical device for objectively grading rhytid severity prior to treatment together with allowing the clinician in being able to monitor patient outcomes longitudinally (Fabi et al., 2012 and Vanaman et al., 2015).

With the advent of more advanced formulations in HA dermal technology my colleague and I AMH focused our attention on the use of such fillers to address rhytides of the décolletage and to carry out a natural lip augmentation. We chose TEOSYAL Redensity II to augment the décolletage and the new formulation TEOSYAL KISS as part of the case studies.

TEOSYAL Redensity II has a HA concentration of 15mg/ml, contains 0.3% lidocaine and is a mixture of non-cross-linked and cross-linked HH containing the Dermo-Restructuring Complex. We chose this to carry out one of the two case studies to examine whether we could successfully rejuvenate the décolletage area naturally. In addition we used TEOSYAL KISS which has a HA concentration of 25mg/ml, 0.3% lidocaine and is composed exclusively of BDDE cross-linked HA.

All patients underwent a clinical history, were consented and photographs taken before and after the procedure. A topical anaesthetic was used in each case prior to administration of the HA filler. Importantly, it should be noted that in Caucasian patients, the epidermis and dermis have been reported to be 39–44 μm and 1319–1400 μm thick, respectively in the décolletage area. The chest also demonstrates variable distribution of subcutaneous fat and decreased pilo-sebaceous units compared with facial skin, as a direct result particular care needs to be used when injecting this area.


The rate of change of formulations has been every increasing in the development of HA dermal fillers. As the technology grows continues the next installment will likely see further additional synergistic component will likely be merged with the underlying HA platform, as seen with the Dermo-Restructuring Complex. This will no doubt have a positive impact with longer lasting, more visco-elastic, cohesive and integrated HA fillers which will deliver natural results (case studies 1 and 2) with a skilled practitioner in the future.


Alexandra and I would like to take this opportunity in dedicating this article to our family and friends both past and present, with particular reference to Mr William Mills and Dr Sayyid Azizul Haq.

Mrs Alexandra Mills Haq is a Nurse Practitioner, and  Founder of AM Aesthetics Belmont Road Belfast E:

Professor Syed Haq is a is a Consultant Physician and Founder of The London Preventative Medicine Centre. E:; W:

Author: bodylanguage

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