Busso M et al. PRIME North America 2014; 2(2): 42-8

1. Reengineering injectable
hyaluronic
acidfillers:
the scienceMarianoBusso,DavidApplebaum,ThomasTzikas,BirgitLundskovFuhlendorff,
andJamesFinneyexploretheuseofBacillussubtilisasanovelbacterialsourceof
hyaluronicacidforinjectablesofttissuefillersusedinaestheticmedicine
42 March/April 2014 |prime-journal.com
peer-review | injectable treatments |

2. ABSTRACT
Aesthetic medicine is dedicated to satisfying the aesthetic goals of
patients, while optimising outcomes and minimising adverse events.
Soft tissue fillers are now the second most commonly performed
minimally-invasive procedure in aesthetic medicine. Hyaluronic acid
(HA) is the most abundant glycosaminoglycan in the human dermis,
and it is the injectable biomaterial of choice for this use. Procedures
using HA fillers are predicted to increase in frequency by 8–12% per
year in North America alone1
. A primary challenge for manufacturers
of soft tissue fillers has been to obtain HA of high quality and purity.
HA is currently derived from three sources: the rooster comb of male
chickens, the bacterium Streptococcus equi subsp zooepidemicus,
and — most recently — the bacterium Bacillus subtilis, first available
in 2011. The B. subtilis-derived HA process allows for a high level of
purity and a homogeneous end-product because it does not require
the use of powerful organic solvents to extract it from the bacterial
capsule, in contrast to the process required for Streptococcus-
derived HA. Adverse events are generally injection-related and
not serious or systemic. B. subtilis-derived HA is well placed in the
market to complement existing sources of HA used in soft tissue
fillers.
Keywords
aesthetic medicine, Bacillus
subtilis, hyaluronic acid, Bacillus
subtilis-derived fillers, soft tissue
fillers, fillers, facial injectables
Mariano Busso, MD, FAAD,
Dermatologist, Coconut Grove,
FL; David Applebaum, MD,
FACS, Plastic Surgeon, Boca
Raton, FL; Thomas Tzikas,
MD, Facial Plastic Surgeon,
Delray Beach, Fl; Birgit
Lundskov Fuhlendorff,
Head of Technical Service,
Novozymes Biopharma DK
A/S, Bagsvaerd, Denmark;
James Finney, MSc, PGCert,
Project Manager, Novozymes
Biopharma UK Ltd, Nottingham,
UK
email: drbusso@aol.com;
biopharma@novozymes.com
outcomes. Health professionals practicing aesthetic
medicine (dermatologists, plastics surgeons, and other
aesthetic medicine providers) are trained in both
invasive and non-invasive treatment modalities, and
typically use a combination of both to meet the needs of
the patient.
Biomaterials and their aesthetic
application
The International Union of Pure and Applied Chemistry
(IUPAC) defines biomaterial as ‘material exploited in
contactwithlivingtissues,organismsormicroorganisms’2
.
However, a clearer definition may be ‘any synthetic
material that is used to replace or restore function to a
body tissue and is continuously or intermittently in
contact with body fluids’3
.
There are many different types of materials (metals
and alloys; ceramics and glasses; polymers; composites)
thatcanbeusedinavarietyofmedicalordentalsettings2
.
Biomaterials used within the field of minimally‑invasive
aesthetic medicine are typically injectable.
An ideal injectable biomaterial used as a facial soft
tissue filler should be non-allergenic, non-carcinogenic,
non-immunogenic, non-migratory, and
non‑teratogenic4, 5
. An ideal injectable biomaterial should
also be reversible, long-lasting but not permanent, and
versatile in its application, and it should possess
reproducible safety outcomes4, 5
. Hyaluronic acid (HA)
A
esthetic medicine is focused
on satisfying the aesthetic desires
and goals of patients. Procedures in
this area are generally elective and are
dedicated to the dual goals of
optimising patient outcomes and
minimising adverse effects.
This rapidly emerging specialty is primarily focused
on the pathophysiology and mechanobiology of facial
ageing and adheres to science and evidence-based
prime-journal.com |March/April 2014 43
| injectable treatments | peer-review

3. The expanding use of soft tissue
fillers in aesthetic medicine
Soft tissue fillers are now the second most commonly
performed minimally-invasive procedure behind
botulinum toxin injections9, 10
. According to the American
Society of Plastic Surgery (ASPS), approximately
2 million procedures were performed using soft tissue
fillers in 2012, and the facial injectable market is
estimated to be worth $1 billion in 20131, 11
. Procedures
using HA soft tissue fillers are predicted to increase in
frequency by 8–12% per year in North America alone1, 11
.
Drivers for this growth include greater awareness and
acceptance of aesthetic medicine, improved
accessibility to practitioners in the field, an ageing
population, and the opportunity for individuals to
increase their general wellbeing.
Sources of HA soft tissue fillers
HA soft tissue fillers are currently derived from three
sources. The first source, the rooster comb of male
chickens, is now largely an historic source; HA derived
from this method is currently used in only a small
number of US proprietary products designed for
non‑aesthetic use6, 12
.
Most HA used in aesthetic medicine today is derived
from the bacterium Streptococcus equi subsp
zooepidemicus(ofvariousstrains)5, 12
.Streptococcus‑derived
HA is well established in the worldwide aesthetic market,
having been used for over two decades with catalogued
efficacy and safety data. Even so, S. equi is considered a
pathogen in horses, and there are a number of
potential disadvantages of this source, such as
trace residual endotoxin and lack of uniformity
in HA molecular weight and strand length12, 13
.
For example, Restylane® (manufactured by
Q-Med, a Galderma division, and
distributed in the US by Medicis, a
division of Valeant Pharmaceuticals) is
a Streptococcus-derived HA product,
which was initially associated with a
hypersensitivity reaction frequency of
0.8% pre-200014
. However, after
improvements in the manufacturing
process that led to a raw product
containing less protein, this incidence
decreased to 0.6% post-200014
. To that end,
alternative production sources have been
explored to negate these potential
disadvantages12
.
The newest source of HA is from the bacterium
Bacillus subtilis, first available in 2011 as Hyasis®
(manufactured by Novozymes Biopharma DK A/S.,
Bagsvaerd, Denmark)5, 12
. (Currently, Enhancement
Medical, LLC, Wauwatosa, WI is manufacturing B.
subtilis-derived HA injectable gel under the trade
name Expression. As of January 2014, Expression
has a Food and Drug Administration (FDA)
indication for use as an intranasal splint, but it is
used off‑label in aesthetic medicine with no
official aesthetic indication.)
demonstrates all of these beneficial attributes;
therefore, it is currently the biomaterial of choice in
aesthetic medicine.
The link: HA and aesthetic medicine
HA, a complex sugar, is the most abundant
glycosaminoglycan in the human dermis5
.
Approximately half of the 14–16 g of HA in the
human body is found in the cell surface
and extracellular matrix of the skin6
. It is
the major component of the vitreous
humour in the eye (0.1 mg/mL), and
large concentrations are found in the
cartilage and synovial fluid of the
joints.
HA can be considered to have
both biological and mechanical
functions in the human body6
.
Biologically, it regulates cell
proliferation and migration, as well as
angiogenesis5
. In a mechanical
capacity, HA maintains volume by
drawing water into the skin and other
structures; it also cushions, protects, and
supports by binding collagen and elastin fibres5
.
Aesthetic medicine uses the mechanical properties
of HA with the aim of restoring this function that may
degenerate over time. HA-based soft tissue fillers are
typically used in the face in such areas
outlined in Table 1. Other, less common
areas of treatment include reshaping the
nose, recontouring the forehead, and
revolumising earlobes. In addition, HA
fillers have been used to rejuvenate the
hands and the décolletage8
.
Table 1 Typical areas of use for HA fillers in
aesthetic medicine5, 7
Section of face Area
Upper face n Eyebrows
n Forehead lines
n Forehead recontouring
n Glabellar lines
n Periocular areas
n Temple lipoatrophy
Mid face n Earlobes
n Medial/lateral malar cheek
augmentation
n Nasojugal groove augmentation
n Nasolabial folds
n Tear trough
Lower face n Lip and perioral area (restoration or
augmentation)
n Oral commissures
n Marionette lines (corners of the
mouth)
n Mentalis crease of chin
n Jawline or prejowl sulcus areas
Other areas n Décolletage
n Hands
Figure 1 Bacillus
subtilis morphology
The Bacillus subtilis-derived
HA offers a number of
bioprocessing advantages over
Streptococcus-derived HA.
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44 March/April 2014 |prime-journal.com

4. Figure 2 Diagram comparing Streptococcus
and Bacillus hyaluronic acid fermentation
The B. subtilis-derived HA offers a number of
bioprocessing advantages over Streptococcus-derived
HA. In the Streptococcus-based process, HA is produced
by the cells and surrounds the bacterial capsule. In order
to liberate HA, the cells have to be physically disrupted:
sonicated or homogenised, depending on the
methodology. This results in a lack of uniformity in the
resulting HA, so there is a wider range of molecular
weights and chain lengths. When compared with the
Bacillus process, which secretes HA, there is a narrower
range of molecular weights (~850 MDa) and chain length,
hence more uniformity in the final product.
Furthermore, in contrast to Streptococcus, which
requires use of organic solvents to separate or extract
HA from the bacterium cell surface, B. subtilis-derived
HA is secreted directly into the medium from the host
bacterium5
. As such, the HA from B. subtilis can be
separated from the host cell without the use of organic
solvents. In order to physically separate the HA in the
Streptococcus-derived process, organic solvents have to
be used. In most of the methodologies reviewed, this
requires a large volume of solvent. In the Bacillus-derived
HA process, the elimination of the organic solvents
reduced the costs and also increased the sustainability
of the process because it is a 100% water-based process.
The organic solvents are recovered in the Streptococcus
process, but the solvents can affect the structure of the
HA molecules. This can affect the bioprocessing of the
final end product and steps must be taken to adjust for
the presence of solvent, which could affect cross-linking
and other properties. Whether this has a true effect in
clinical translation is not known and will have to be
further elucidated. Therefore, by eliminating organic
solvents in the Bacillus-process, a ‘cleaner’ end product is
the result.
There are a number of other source organisms (e.g.
Agrobacterium sp, Escherichia coli, and Lactococcus lactis)
from which HA can be derived, but many of these are
restricted to laboratory-based primary research12
.
Currently,B. subtilisandS. equiaretheonlytwoorganisms
in use on a commercial scale12
.
Bacillus subtilis: a microbial mini
factory?
B. subtilis, first identified in 1835, was one of the first
bacteria ever studied in microbiology (Figure 1). It is
found naturally in soil, but also resides in the digestive
tract of some animals15, 16
. It is one of the most well
characterised bacterial organisms in nature from a
biotechnological perspective. The literature has
evaluated its probiotic activity against the common
digestive pathogens Helicobacter pylori and
Enterobacteriaceae, which illustrate the varying
dynamics of this organism16
. Widely used in science and
technology and having been granted ‘Generally
Recognized As Safe’ (GRAS) status by the FDA, it is seen
as an ideal host for production of HA6, 17
.
The fermentation process using B. subtilis offers
inherent bioprocessing advantages over
Streptococcus‑derived HA (Figure 2). B. subtilis-derived
HA is expressed from the cell into the fermentation
environment; it is then separated without the use of
organic solvents and spray-dried, making it a completely
100% water-based process. In contrast, in the
Streptococcus processing model, the HA grows and
surrounds the bacterial capsule and must be extracted
using organic solvents (2-propanol and sodium acetate)
to disrupt the cells to liberate HA6
. This creates a number
of processing difficulties, including a risk for the
inclusion of trace bacterial endotoxins, cellular debris,
and solvents when the HA is extracted, which limits its
application in the biomedical field12
. In contrast, B.
subtilis-derived HA does not produce endotoxins6
. In
addition, the Bacillus model produces more
homogenous strands of HA as compared with
Streptococcus-derived HA.
Bioengineering injectable
biomaterials for soft tissue fillers
Most of the currently available HA injectable
biomaterials used in soft tissue fillers consist of particles
(a solid phase) suspended in a fluid phase18
. The
physicochemical structure of this soft tissue filler is
established during the manufacturing process by the
adjustment of a number of variables including, but not
limited to:
■■ Concentration of the solid-phase particles
■■ Method and percentage of cross-linking of the
solid‑phase particles
■■ Type and technology of cross-linker used
■■ Proportion of gel in the fluid phase (gel-to-fluid ratio).
HA soft tissue fillers with different physicochemical
properties produce different clinical outcomes with
regard to their rheology — elasticity and viscosity18
. One
important rheological property of a soft tissue filler gel
B. subtilis-
derived HA is
expressed from
the cell into the
fermentation
environment; it is
then separated
without the use of
organic solvents
and spray-dried,
making it a
completely 100%
water-based
process.e
Bacillus fermentation
100% water based process
Bacillus subtilis
HA secreted into medium
Gentle physical separation
Steptococcus fermentation
Organic solvent based process
Streptococcus equi subspecies
HA produced and surrounds
the bacterial capsule
Cellular disruption to liberate HA
Organic solvent precipitation to recover HA
Risk of residual endotoxin
Less homogenous HA strands More homogenous HA strands
No use of organic solvents to recover HA
B. subtilis strain does not produce endotoxin
HA
production
Recovery
and
purification
Resulting HA
macromolecules
Microbial
strain
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46 March/April 2014 |prime-journal.com

5. that can be quantified is its elastic modulus (G’). A high G’
in a HA soft tissue filler appears to be a predictor of a
better resistance to skin tension forces; therefore, it
deforms less under pressure18
.
The rheological properties can
be used as a scientific rationale in
choosing a soft tissue filler — a
strategy known as rheological
tailoring18
. This can be
individualised for each patient
and facial area to achieve the
desired goals and outcomes. To
that end, viscosity and elasticity
should be part of the selection
process when choosing an
appropriate soft tissue filler. Other
clinical considerations, such as
injection technique and implantation depth of soft tissue
filler, are also important18
. The addition of B. subtilis-
derived HA to aesthetic medicine practitioners’
armamentarium can increase their ability to achieve
customised, evidence-based outcomes from a
rheological perspective.
Potential complications associated
with injectable HA biomaterials
As with every medical procedure, there is a degree of
risk associated with the use of injectable HA soft tissue
fillers, although serious complications arising from
their use are infrequent19
. Unwanted adverse events
do occur with all soft tissue filling compounds
(including HA biomaterials); however, their true
prevalence is unknown4, 20–22
. These adverse events
may be injection‑related, technique‑related, or
(rarely) may be owing to localised exposure to HA
itself, potential residual purification solvents, or
trace presence of endotoxin. Injection-related
events are those that are caused by the injection of
the soft tissue filler rather than the soft tissue filler
itself, while technique-related events are the result
of the specific manner in which a physician injects
the substance into the patient.
Injection-related adverse events
By far the most common adverse events
associated with HA soft tissue fillers are injection-
related19
. These events are usually transient,
resolving within 4–7 days, and are localised to the site
ofinjection(Table 2).Rarely,aninadvertentintravascular
injection or adjacent vascular compression may result in
a non-localised adverse event (i.e. necrosis)19, 23
.
Technique-related adverse events
One of the most common technique-related adverse
events is inappropriate placement of the soft tissue filler.
Lumps of visual product or bluish bumps under the skin
(the Tyndall effect) can result from a too superficial
placement of product24, 25
. For the most part, such
reactionscanbepreventedbytheuseofcorrectinjection
technique and proper training on the part of the injector19
.
The occurrence of these events can lead to anxiety,
dissatisfaction, and less than optimal results for the
patient24, 25
. The advantage of HA-based soft tissue fillers
over other classes (e.g. Poly-L-lactic acid, Calcium
n Swelling n Hyperaemia/erythema
n Local oedema n Pain/tenderness
n Contusions (bruising) n Pruritis (itching)
Table 2 Injection-related adverse events
associated with HA-based fillers19, 23
As with every medical
procedure, there is a degree
of risk associated with the
use of injectable HA soft
tissue fillers, although
serious complications
arising from their use
are infrequent
| injectable treatments | peer-review

6. References
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3. Davis JR. ed, Handbook of Materials for
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4. Alijotas-Reig J, Fernández-Figueras MT, Puig
L. Late-onset inflammatory adverse reactions
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5. Brandt FS, Cazzaniga A. Hyaluronic acid gel
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8. Streker M, Reuther T, Krueger N, Kerscher M.
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9. Ozturk CN, Li Y, Tung R, Parker L, Piliang MP,
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10. American Society for Aesthetic Plastic
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14. André P. Evaluation of the safety of a
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vitro anti-Helicobacter pylori activity of the
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secretion of antibiotics. Antimicrob Agents
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Microorganisms & Microbial-Derived Ingredients
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nqmu5r7 (accessed 25 February 2014)
18. Sundaram H. Going With The Flow: An
Overview of Soft Tissue Filler Rheology and its
Potential Clinical Applications, Part I. http://
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2014)
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Ratziu V, Chosidow O. Facial cosmetic filler
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2008; 217(1): 81–4
22. Alijotas-Reig J, Garcia-Gimenez V. Delayed
immune-mediated adverse effects related to
hyaluronic acid and acrylic hydrogel dermal
fillers: clinical findings, long-term follow-up and
review of the literature. J Eur Acad Dermatol
Venereol 2008; 22(2): 150–61
23. Gilbert E, Hui A, Meehan S, Waldorf HA. The
basic science of dermal fillers: past and present
Part II: adverse effects. J Drugs Dermatol 2012;
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24. Narins RS, Jewell M, Rubin M, Cohen J, Strobos
J. Clinical conference: management of rare
events following dermal fillers -- focal necrosis
and angry red bumps. Dermatol Surg 2006; 32(3):
426–34
25. Brody HJ. Use of hyaluronidase in the
treatment of granulomatous hyaluronic acid
reactions or unwanted hyaluronic acid
misplacement. Dermatol Surg 2005; 31(8 pt 1):
893–7
26. Dougherty AL, Rashid RM, Bangert CA.
Angioedema-type swelling and herpes simplex
virus reactivation following hyaluronic acid
injection for lip augmentation. J Am Acad
Dermatol 2011; 65(1): e21–2
27. He MS, Sheu MM, Huang ZL, Tsai CH, Tsai RK.
Sudden bilateral vision loss and brain infarction
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JAMA Ophthalmol 2013; 131(9): 1234–5
28. Chader H, Bose R, Hersant B et al. Infectious
cellulitis of the face complicating injection for
aesthetic nasolabial sulcus by hyaluronic acid:
about seven cases. Ann Chir Plast Esthet 2013;
58(6): 680–3
29. Kwon SG, Hong JW, Roh TS, Kim YS, Rah DK,
Kim SS. Ischemic oculomotor nerve palsy and
skin necrosis caused by vascular embolization
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30. Alijotas-Reig J. Recurrent urticarial vasculitis
related to nonanimal hyaluronic acid skin filler
injecction. Dermatol Surg 2009; 35(Suppl 1):
395–7
31. McGuire LK, Hale EK, Godwin LS. Post-filler
vascular occlusion: a cautionary tale and
emphasis for early intervention. J Drugs
Dermatol 2013; 12(10): 1181–3
32. Glaich AS, Cohen JL, Goldberg LH. Injection
necrosis of the glabella: protocol for prevention
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33. Alam M, Gladstone H, Kramer EM et al. ASDS
guidelines of care: injectable fillers. Dermatol
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hydroxylapatite) is their reversibility when treated
with hyaluronidase, which can successfully resolve
many unwanted adverse events20, 25
.
Serious adverse events related to HA
Injectable HA soft tissue fillers are typically well tolerated
with few adverse events. Serious events are possible,
although rare. Typically these events have not been
associated with aesthetic use of HA products.
HA-derived injectable soft tissue fillers may rarely be
associated with localised reactions, such as persistent
swelling, pain, and nodule formation. These effects may
require physical removal and/or enzymatic degradation
with hyaluronidase4, 19
. Other rare effects include
angioedema, arterial occlusion, loss of vision, infection,
necrosis, vasculitis and vascular occlusion23, 26–31
.
Practitioners should be able to recognise these adverse
events and apply the appropriate clinical algorithm for
treatment should they occur9, 31–33
.
Conclusions
A primary challenge for manufacturers of soft tissue
fillers has been obtaining HA of high quality and purity.
Contrary to Streptococcus-derived HA, B. subtilis-derived
HA is produced by a host, free of endotoxin and without
organic solvents.
The B. subtilis-derived HA process overcomes the
manufacturing and safety challenges associated with HA of
other origins, allowing for a high level of purity and a
homogeneous end-product. The bioengineering process
associated with production of B. subtilis-derived HA does
not require the use of powerful organic solvents to extract it
from the bacterial capsule, in contrast to the process
requiredforStreptococcus-derivedHA.Inaddition,B.subtilis-
derived HA results in uniform strands and has a
homogenous molecular weight with a narrow and well-
Most hyaluronic acid
(HA) used in aesthetic
medicine today is
derived from
Streptococcus sp
The newest source of
HA is from Bacillus
subtilis
A primary challenge
for manufacturers of
soft tissue fillers has
been to obtain HA of
high quality and purity
The B. subtilis-
derived HA process
allows for a high level of
purity and a
homogeneous
end-product
B. subtilis-derived HA
is well placed in the
market to complement
existing sources of HA
used in soft tissue fillers
Key points
defined weight distribution. In summary, B. subtilis-derived
HA is well placed in the market to complement existing
sources of HA used in soft tissue fillers.
 Declarations of interest Dr Mariano Busso is a
consultant for Merz Aesthetics; Dr David Applebaum is a
consultant and speaker for Valeant Pharmaceuticals; Dr
Thomas L. Tzikas is a shareholder of Enhancement
Medical; Birgit Lundskov Fuhlendorff is an employee of
Novozymes Biopharma DK A/S; and James Finney is an
employee of Novozymes Biopharma UK Ltd
 Figures 1 © Sebastian Kaulitzki; 2 Original chart data
courtesy of Novozymes Biopharma UK Ltd, Nottingham,
UK, reproduced by Prime Journal
A primary
challenge for
manufacturers of
soft tissue fillers
has been obtaining
HA of high quality
and purity.
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