Scientific
`Research
`Publishing
`
`Materials Sciences and Applications, 2019, 10, 423-431
`Materials Sciences and Applications, 2019, 10, 423 -431
`http://www.scirp.org/journal/msa
`http: / /www.sci rp.org/lournal /msa
`ISSN Online: 2153-1188
`ISSN Online: 2153 -1188
`ISSN Print: 2153-117X
`ISSN Print: 2153 -117X
`
`Viscoelastic Evaluation of Different Hyaluronic
`Viscoelastic Evaluation of Different Hyaluronic
`Acid Based Fillers Using Vibrational Optical
`Acid Based Fillers Using Vibrational Optical
`Coherence Tomography
`Coherence Tomography
`
`Frederick H. Silver1,2*, Ruchit G. Shah3, Nikita Kelkar2,
`Frederick H. Silverl,2*, Ruchit G. Shah3, Nikita Kelkar2,
`Dominick Benedetto4, Dale DeVore5, Justin Cohen6
`Dominick Benedetto4, Dale DeVore5, Justin Cohen6
`
`1Department of Pathology and Laboratory Medicine, Robert Wood Johnson Medical School, Rutgers, The State University of New
`Jersey, Piscataway, NJ, USA
`2OptoVibronex, LLC, Mt. Bethel, Pa, USA
`3Graduate Program in Biomedical Engineering, Rutgers, The State University of New Jersey, Piscataway, NJ, USA
`4Center for Advanced Eye Care, Vero Beach, FL, USA
`5DV Consulting, Chelmsford, MA, USA
`6Glasgold Group, Princeton, NJ, USA
`Email: *fhsilver @hotmail.corn
`
`How to cite this paper: Silver, F.H., Shah,
`R.G., Kelkar, N., Benedetto, D., DeVore, D.
`and Cohen, J. (2019) Viscoelastic Evalua-
`tion of Different Hyaluronic Acid Based
`Fillers Using Vibrational Optical Cohe-
`rence Tomography. Materials Sciences and
`Applications, 10, 423-431.
`https://doi.org/10.4236/msa.2019.105031
`
`Received: April 18, 2019
`Accepted: May 24, 2019
`Published: May 27, 2019
`
`Copyright © 2019 by author(s) and
`Scientific Research Publishing Inc.
`This work is licensed under the Creative
`Commons Attribution International
`License (CC BY 4.0).
`http://creativecommons.org/licenses/by/4.0/
`Open Access
`
`Abstract
`Abstract
`Hylauronic acid (HA) is used as a viscoelastic in Ophthalmology during cat-
`aract surgery based on its high viscosity at rest, its ability to shear thin and
`dissipate energy during phacoemulsification. However, these properties of
`HA solutions would make them susceptible to migration when used as der-
`mal filler materials. In this study, we apply a new technique termed vibra-
`tional optical coherence tomography (VOCT) to compare the physical prop-
`erties of different HA solutions and fillers used in facial aesthetics. Results
`presented in this study suggest that HA solutions and HA dermal fillers have
`markedly different physical properties. HA solutions are highly viscoelastic
`with high % viscous losses while fillers tend to have lower viscous energy dis-
`sipation properties. Clinical observations suggest that the high loss fillers are
`injected more superficially in the face where tension and internal and external
`forces are more likely minimized giving tissue of the hands and lips more vo-
`lume and allowing more natural movement. In contrast, the lower loss gels
`that are used to lift tissue, generally have a higher G’, and are injected deeper
`into the face where injection and internal forces are likely to be higher. It is
`concluded that HA filler gel design can be optimized by use of VOCT to eva-
`luate the % viscous energy loss both in vitro and in vivo.
`
`Keywords
`Keywords
`Hyaluronic Acid, Injectable Filler, Dermal Filler, Plastic Surgery, Cosmetic
`
`DOI: 10.4236/msa.2019.105031 May 27, 2019
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`423
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`Materials Sciences and Applications
`Materials Sciences and Applications
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`Proii2r71lr? Y, Ailerÿarr
`IPR201 9-0 1 600, eral.
`DeVore epo. Ex. 48
`
`ALL 2148
`PROLLENIUM V. ALLERGAN
`IPR2019-01505 et al.
`
`

`

`F. H. Silver et al.
`
`Surgery, Viscoelastic, Mechanical Properties, Facial Surgery, Optical Coherence
`Tomography, Vibrational Optical Coherence Tomography
`
`1. Introduction
`Hyaluronic acid (HA) also known as hyaluronan, is polysaccharide composed of
`repeating β-1-4-linked D-glucuronic acid and β-1-3-linked N-acetyl-D-glucosamine
`disaccharide units [1]. The various names of HA reflect the properties of the
`molecule under various conditions. At neutral pH, HA exists as a polyelectrolyte
`with associated cations, frequently as a sodium salt; therefore, the name sodium
`hyaluronate. The name was later amended to “hyaluronate” in reference to its
`salt form or “hyaluronan,” a term used to encompass all forms of the molecule
`[1].
`HA is found ubiquitously in the ECM of all vertebrate tissues including blood,
`synovial fluid, vitreous body, pericellular matrix, cytoplasm, and nucleus. Its use
`as a viscoelastic in Ophthalmology during cataract surgery is based on the mo-
`lecule’s ability to shear thin and thereby absorb energy during phacoemulsifica-
`tion [2]. This property is a result of the reversible hydrogen bonding that occurs
`between side chains of the molecule [2]. However, to limit its ability to shear
`thin and flow under applied stress requires the formation of covalent crosslinks
`between HA chains.
`Hyaluronic acid (HA) injectable dermal fillers (DFs) have become the most
`popular agents for soft tissue contouring and volumizing. HA fillers are reported
`to be characterized by ideal properties such as biocompatibility, biodegradabili-
`ty, and versatility. These filler properties enable HA DFs to dominate and revo-
`lutionize the filler market with numerous products differing in HA sourcing,
`degree of crosslinking, concentration, hardness, cohesiveness, and consistency.
`The inclusion or lack of inclusion of an anesthetic, indications for use, and lon-
`gevity of correction are other variables examined in designing DFs [3] [4].
`However, there are potential complications that can arise from use of these ma-
`terials [5] [6].
`The rheological and mechanical properties of HA fillers have been reviewed
`recently [4]. HA fillers have been developed that are both viscous solutions and
`solution-gel mixtures containing uncrosslinked and crosslinked macromole-
`cules. HA fillers are crosslinked using a number of different crosslinking agents.
`The HA concentration of fillers ranges from 5.5 to 28 mg/ml, % crosslinking
`from 0 to 20%, shear elastic modulus from 100 to 1800 Pa, and particle size from
`0 to over 1050 micrometers [4]. Observations of the physical properties of HA
`solutions and gels are important parameters that control the behavior of fillers in
`clinical use. However, currently, there are no tests available to study the physical
`properties of fillers both before and after implantation. We have developed a
`new technique termed vibrational optical coherence tomography (VOCT) that
`
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`can be used to evaluate HA filler properties both in vitro and in vivo.
`The purpose of this paper is to introduce the use of VOCT to evaluate the
`physical properties of HA fillers before clinical use. VOCT has been used to eva-
`luate the properties of skin and scar tissue in vivo [7]-[14], it can also be used to
`evaluate the mechanical behavior of skin after filler injections. Characterization
`of filler viscoelastic properties is needed to determine the desired clinical out-
`come; how the starting HA filler properties influence the quality of the outcome
`is a question that needs to be answered.
`
`2. Materials and Methods
`VOCT is new technique that measures the resonant frequency and viscous losses
`of solutions of macromolecules and gels. Unlike measurement of solution vis-
`cosity or viscoelasticity using a viscometer, this technique provides measures of
`both cohesive as well as viscous energy dissipation of materials when a mechan-
`ical vibration is applied. This method can be used both in vitro and in vivo
`unlike a viscometer which can only be used in vitro [7]-[14].
`Commercial samples of pure HA with molecular weights of 5 k and 1.8 M
`were obtained from Lifecore Biomedical, LLC. (Chaska, Mn). Samples of dermal
`fillers listed in Table 1 were obtained from Allergan Inc. (Dublin, Ire). A drop
`containing between 0.1 and 0.2 ml of each sample was placed on a glass slide for
`examination. The slide was the placed on a rigid frame that had a hole cut out so
`that the sound was applied to the slide from below. The sample volume did not
`influence the measurement of resonant frequency. Samples were tested at 22˚C
`by applying a sinusoidal sound wave from a speaker placed beneath the sample
`as discussed previously [7]-[14]. The frame, speaker, and glass slide resonant fre-
`quencies were measured in the absence of the samples. Sample weighted displace-
`ments were corrected for any resonant frequencies of the speaker and support
`
`Table 1. HA formulations studied using vibrational optical coherence tomography.
`The % viscous loss is reported at 30 Hz for the HAs studied.
`
`Sample
`
`Conc (mg/ml)
`
`Resonant Freq (Hz) Viscous Loss (%)
`
`Clinical Use
`
`Restylane D
`
`Restylane Lft
`
`Voluma XC
`
`Vollure XC
`
`Restylane L
`
`Juvederm U
`
`Restylane S
`
`HA (5 k)
`
`HA (1.8 M)
`
`20
`
`20
`
`20
`
`17.5
`
`20
`
`24
`
`20
`
`20
`
`20
`
`150
`
`140
`
`150
`
`150
`
`150
`
`140 - 180
`
`180
`
`140
`
`220
`
`27
`
`27
`
`25
`
`35
`
`35
`
`40
`
`40
`
`60
`
`60
`
`md/deep
`
`md/deep
`
`md/deep
`
`sup/md/deep
`
`sup/md/deep
`
`md/sup
`
`sup
`
`N/A
`
`N/A
`
`Note: the standard deviation of resonant frequency measurements is about 6 Hz while that for % viscosity
`measurements is about 10% of the % reported. Abbreviations: sp = superficial, md = mid, N/A = not appli-
`cable, Freq = resonant frequency, Conc = concentration.
`
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`materials, or from line voltage variations.
`Transverse forces were applied to the sample by positioning an acoustic
`loudspeaker (Intervox S225RA-40) beneath the sample. A function generator
`(Agilent) was used to drive the speaker with sinusoidal waveforms at varying
`amplitudes and frequencies. The resonant frequency was determined as the fre-
`quency at which the maximum displacement was observed [7]-[14].
`Transverse sample displacement was measured by spectral-domain optical
`coherence tomography (SD-OCT), a non-contact, interferometric technique
`[7]-[14]. The resonant frequency of each sample was initially estimated at a sin-
`gle point by measuring the transverse displacement resulting from sinusoidal
`driving frequencies ranging from 20 Hz to 500 Hz, in steps of 50 Hz. Once the
`region where the maximum displacement was identified, smaller steps of 10 Hz
`were used to more accurately identify the peak frequency and the actual reso-
`nant frequency, fn.
`Measurement of Elastic and Viscous Behaviors
`The elastic and viscous components of the viscoelastic behavior were obtained
`from measurements made from the driving frequency peak as described pre-
`viously [7]-[14]. The elastic component was obtained from the peak height while
`the viscous component was obtained by dividing the change in frequency at the
`half height of the peak (i.e. 3 db down from maximum peak in power spectrum)
`by the driving frequency. This method is known as the half-height bandwidth
`method discussed by Paul Macioce
`(http://www.roush.com/wp-content/uploads/2015/09/Insight.pdf). The viscous
`loss in percent for each sample was tabulated as a function of the applied sound
`frequency.
`
`3. Results
`Weighted displacement versus frequency plots for droplets of pure HA with
`molecular weights 5 k and 1.8 M are shown in Figure 1. Major peaks are shown
`at frequencies of 140 Hz (Mw = 5 k) and 220 Hz (Mw = 1.8 M). The % viscous
`contribution to the viscoelastic behavior is shown in Figure 2. Both pure HA
`samples, independent of molecular weight, have viscous losses that are about
`60% at 30 Hz suggesting that these materials are more viscous than elastic at low
`frequencies. At frequencies above 200 Hz, these HAs have % viscous losses that
`approach 10% and behave almost purely elastically. In the absence of crosslinks,
`HA molecules are highly mobile and do not remain in place when an applied
`force is exerted on their surfaces.
`Weighted displacement measurements versus frequency for representative
`dermal fillers listed in Table 1 are shown in Figure 3 and the % loss behavior for
`typical dermal fillers examined in this study are shown in Figure 4. The
`weighted displacement versus resonant frequency curves for all the filler materials
`exhibit resonant frequencies that center around 150 Hz. The percent loss behaviors
`of the fillers fall into the two groups the group with losses from about 35% to
`
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`40% at 20 Hz (group A) and those with losses of about 25% (group B) at 20 Hz.
`At high frequencies the % loss decreases to about 5% for all the dermal filler
`samples studied. At high frequencies all fillers behave almost purely elastic. Note
`the gel dermal fillers that are used in cosmetic surgery are more elastic (less
`
`t 1.8M
`-a-5k
`
`
`
`9
`
`8
`
`2
`
`1 0
`
`0
`
`50
`
`100
`
`150
`
`200
`
`250
`
`Frequency (Hz)
`Figure 1. Plot of weighted displacement versus frequency for a drop of purified HA solution with molecular weights of 5 K and
`1.8 M. The major peaks are seen at 140 Hz (Mw = 5 k) and 220 Hz (Mw = 1.5 M) for a drop of solution on a glass slide. Note the
`non-major peaks arise from multiple vibrations associated with within the droplet that occur during energy dissipation.
`
`
`70
`
`60
`
`50
`
`co 40
`oJ
`
`c° 30
`w
`
`20
`
`10
`
`00
`
`50
`
`100
`
`150
`
`200
`
`250
`
`Frequency (Hz)
`Figure 2. % Viscous loss as a function of frequency for a drop of purified HA solutions. Note the % viscous loss of low (5 k) and
`high (1.8 M) molecular weight HA fractions are very high at low frequency (60%) and approach a value of 10% at high frequen-
`cies. At low frequencies HA solutions are viscous liquids that dissipate energy by shear thinning.
`
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`
`t Vollure XC
`t Voluma XC
`f Restylane
`
`F. H. Silver et al.
`F. H. Silver et al.
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`200
`
`180
`
`160
`
`. 140
`
`120
`
`aÇi
`
`E8
`
`5 100
`
`aa
`
`)
`rn 80
`
`60
`
`40
`
`20
`
`50
`
`100
`
`150
`
`200
`
`250
`
`Frequency (Hz)
`Figure 3. Typical plot of weighted displacement versus frequency for dermal fillers. Note all dermal fillers had major peaks and
`resonant frequencies at about 150 Hz with several subpeaks being present. Restylane data shown in the figure is for Restylane L.
`
`
`0
`
`0
`
`40
`
`-e- Vollure XC
`f Voluma XC
`t Restylane
`
`30
`
`25
`
`w0
`
`J 20
`
`15
`
`10
`
`0UN
`
`0
`20
`
`40
`
`60
`
`80
`
`100
`200
`120
`
`Frequency (Hz)
`Figure 4. Typical % viscous loss as a function of frequency for dermal fillers. Note the difference between high loss fillers and low
`loss fillers. The high loss group includes Juvederm Ultra, Restylane L, Vollure XC, Restylane Silk. This group had % viscous losses
`in the 35% - 40% range at 20 Hz while the low loss group Voluma XC, Restylane Define, Restylane Lyft and had viscous losses of
`about 25% at 20 Hz. Restylane data shown in the figure is for Restylane L.
`
`
`140
`
`160
`
`180
`
`viscous) at high frequencies than are HA liquid solutions.
`The clinical observations of the uses of the different dermal fillers are shown
`in Table 1. It is observed that group B dermal fillers (Restylane Define, Restylane
`Lyft, Voluma XC), the low loss fillers at low shear rates, are clinically used in the
`mid to deep areas of the skin whereas group A dermal fillers, the high loss fillers
`
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`(Juvederm Ultra, Restylane L, Restylane Refine and Restylane Silk, and Vollure
`XC), are generally used more superficially.
`
`4. Discussion
`HA solutions containing polymeric molecules of different molecular weights are
`biocompatible natural materials that are viscoelastic and shear thin at high shear
`rates [3]. While the biocompatibility of these solutions is an important property,
`the viscoelasticity and liquid-like behavior reflected by the high energy loss at
`low frequencies limits their ability to remain in place as filler materials. There-
`fore modifications must be made to solutions of viscoelastics used in Ophthal-
`mology to make these materials function as dermal fillers that do not migrate
`after injection.
`The most important findings reported in this study, suggest that the viscous
`behavior of pure HA solutions is much higher than that obtained with any of the
`dermal filler materials. While pure HA solutions of low and high molecular
`weights exhibit multiple resonant frequencies, it is clear that uncrosslinked,
`non-particulate containing HA solutions independent of molecular weight be-
`have as highly viscoelastic liquids. The high % loss at low frequencies indicates
`that these materials will absorb energy at low shear rates, dissipating energy as
`needed in cataract surgery. Then at high shear rates they act in an elastic fashion
`and can be removed from the eye via their cohesive forces as a bolus of material.
`In contrast they make poor fillers since they will dissipate energy by migrating in
`an irreversible fashion when an external force is applied to tissue.
`In contrast, HA dermal filler materials are required to remain in place after
`injection even after the application of external forces that occur during sleeping
`or other daily activities. The addition of crosslinks and resulting gel particles de-
`creases the shear thinning of HA and reduces the energy losses and viscoelastic-
`ity of the filler materials. HA dermal fillers can be classified into two groups,
`based on the results reported in this paper: the groups are characterized by dif-
`ferences in the viscous losses at low strain rates. The high loss group includes
`Juvederm Ultra, Restylane L, Vollure XC, Restylane Silk. This group had %
`viscous losses in the 35% - 40% range while the low loss group Voluma XC, Res-
`tylane Define, Restylane Lyft and had viscous losses of about 25%.
`Clinically, the high loss “thinner” gel group has been observed to be more ap-
`propriate for superficial indications to remove fine wrinkles and for lip en-
`hancement. Tissue tension due to forces from collagen fibers along Langer’s
`lines and external forces are more likely to be minimized in these regions of the
`face. In contrast, the lower loss “thicker” DF gels that are used to lift tissue, gen-
`erally have a higher G’, and are injected deeper into the face where volume in-
`duced internal forces are likely to be higher. Optimization in the physical prop-
`erties of the injectable dermal fillers evaluated in this study would be difficult to
`achieve without a multifactorial design that considers concentration, particle
`size, and degree of crosslinking in a single study. Differences in these factors
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`make analysis of the optimization of filler composition and properties difficult to
`achieve.
`
`5. Conclusions
`HA solutions containing polymeric molecules of different molecular weights are
`biocompatible natural materials that are viscoelastic and shear thin at high shear
`rates. While pure HA solutions of low and high molecular weights exhibit mul-
`tiple resonant frequencies, it is clear that uncrosslinked non-particulate con-
`taining HA solutions independent of molecular weight flow easily under applied
`stress that makes them poor filler materials to use for tissue augmentation. The
`addition of crosslinks and gel particles in HA filler materials decreases the shear
`thinning of HA and reduces the energy losses and viscoelasticity.
`Our results suggest that HA fillers can be categorized into two groups. Clini-
`cally, the high loss group has been observed to be used more superficially in the
`face where tissue tension and internal and external forces are more likely mini-
`mized. In contrast, the lower loss gels that are used to lift tissue, generally have a
`higher G’, and are injected deeper into the face where injection and internal
`forces are likely to be higher. Unlike HA dermal filler gels, HA solutions used in
`cataract surgery exhibit high % viscous losses and are not useful in aesthetic
`surgery due to their tendency to migrate under applied internal and external
`forces. Future work will evaluate the % viscous losses of dermal filler materials
`after injection in vivo.
`
`Conflicts of Interest
`The authors declare no conflicts of interest regarding the publication of this paper.
`
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