CLINICAL ▼
Collagen stimulants in facial
rejuvenation: a systematic review
Abstract
Collagen-stimulating agents relating to facial rejuvenation are part of
the family of soft tissue fillers that can be used for facial contouring,
volume restoration and skin rejuvenation through bio-stimulation
of the tissues (Strawford, 2020). Radiesse®, made from calcium
hydroxylapatite, was US Food and Drug Adminstration-approved in
2006. Ellansé®, made from polycaprolactone, was CE-approved in
2009. However, polycaprolactone (which makes up 70% of Ellansé®)
has been an FDA-approved biomaterial since 2001 (Christen and
Vercesi, 2020). This systematic review will evaluate the available
evidence and evaluate if it continues to support the safety and efficacy
of these two facial collagen stimulating materials.
Key words
► Collagen ► Literature search ► Studies ► Ageing process
► Dermal fillers
A
geing is a multifactorial process that
affects different layers of the anatomy
leading to, at the deepest level, bone
resorption and remodelling, resulting in
overlying fat redistribution compounded by fat loss,
muscle atrophy and, at skin level, dermal ageing
through collagen loss. Collagen synthesis stimulants
are, therefore, very attractive solutions to the dermal
aspect of this complex ageing process (Rohrich and
Pessa, 2007; Mendelson and Wong, 2012). Initially,
these agents will always cause a foreign body
reaction when first injected into the host tissue
(Strawford, 2020). Collagen stimulation results as
part of the normal healing response of the body.
After the inflammatory phase, initially producing
type III collagen, microparticles of the filler
become encapsulated as part of a natural protective
mechanism (Strawford, 2020). This mechanism
produces a stable capsule of mainly type I collagen
and lasts as long as the biomaterial is present within
the tissue (Strawford, 2020).
LUCY MILLAR-HUME
Aesthetic nurse specialist, LA Face Consultants, Suffolk
Trainer and qualified educator, LA Face Academy, Suffolk
E: lucy@lafaceconsultants.co.uk
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A systematic review of the literature by Fakhre
et al (2009) reported patient satisfaction regarding
cosmetic treatment experiences using Radiesse®
through a meta-analysis. Results of past outcomes
compared to their institutional study showed
differences in results, and they concluded that, while
it was a viable option for augmentation of facial soft
tissue, accurate large scale population outcome
assessments were mandatory (Fakre et al, 2009).
A 2016 systematic review reported by Shi et al
(evidence level 2) evaluated complications relating
to the injection of calcium hydroxylapatite (CaHA)
for facial soft tissue augmentation (Shi et al,
2016). Only randomised controlled trials (RCTs)
or controlled trials comparing CaHA injection of
the nasolabial fold to either placebo or an active
comparator for facial cosmetic use were included.
Outcome measures were the count and frequency
of complications, which were a range of different
side effects. Subgroups evaluated were CaHA and
lidocaine versus CaHA alone and CaHA versus
hyaluronic acid (HA) filler. Findings supported the
addition of lidocaine to nasolabial fold injection of
CaHA, concluding that there was no significant effect
on oedema, erythema, ecchymosis, pain or pruritus
where lidocaine was added to CaHA for therapy. No
significant difference was proven between CaHA
versus HA for haematomas or nodules. There was
no significant publication bias detected in either
subgroups (Shi et al, 2016).
Methodology and
literature searches
In both cases, the search methodology began with a
strategy to identify any existing systematic reviews
on either substance or brand (as reported above).
Peer-reviewed available evidence found since the last
systematic review in 2016 was gathered by searching
the same databases (i.e. PubMED, EMBASE and
Cochrane, with the addition of CINAHL). Study
inclusion criteria were also repeated from previous
sytematic reviews (i.e. only reporting on RCTs or
© 2020 MA Healthcare Ltd
where there were not any, controlled trials; only
peer-reviewed published data; and only in-vivo
studies relating to facial rejuvenation). Studies in-
vitro, unpublished and/or relating to rejuvenation
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Collagen stimulants for facial rejuvenation can be used for volume restoration and contouring through bio-stimulation of tissues
of any other part of the body were excluded. Some
general articles found through the searches are
considered in the discussion section.
However, medical subject headings searches were
not repeated, rather, title headings using the terms:
‘Radiesse®’, ‘calcium hydroxylapatite’, ‘systematic
review’ and/or ‘meta-analysis’. PubMed returned four
relevant results, and EMBASE and CINAHL each
brought back one relevant result. After duplicates
were removed and abstracts scanned for inclusion
criteria, only two articles were relevant. When the
title term ‘calcium hydroxylapatite’ was searched
with the title search terms, ‘fillers’ and/or ‘dermal
fillers’, PubMed returned a combined nine relevant
results, with a further three from EMBASE and two
from CINAHL. When duplicates were removed, 10
results were relevant to facial rejuvenation between
the databases, but only one met inclusion criteria.
No systematic reviews were found in the Cochrane
Library, but 18 trial results were returned, of which,
three results met inclusion criteria.
PubMed, EMBASE and CINAHL were explored
using and combining the title search terms: ‘Ellanse’,
‘polycaprolactone’, ‘systematic review’ and/or ‘meta-
analysis’. However, no systematic reviews were
found that were relevant to facial aesthetics. When
the title term ‘polycaprolactone’ was searched with
© 2020 MA Healthcare Ltd
the title search terms ‘fillers’ and/or ‘dermal fillers’,
PubMed returned a combined 13 relevant articles,
with a further eight from EMBASE and two from
CINAHL. Once duplicates were removed, only
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020_JOAN_2020_9_8_Collagen stimulants.indd 335
▼ CLINICAL
AdobeStock/Prostock-studio
one article was relevant to inclusion criteria. No
systematic reviews were found in the Cochrane
Library for polycaprolactone either, but 19 trials were
discovered, of which, three results met inclusion
criteria, and one of which was a duplicate of the
aforementioned search.
Results
The results of the search can be seen in Table 1.
Discussion
Evidence comparing CaHA to polycaprolactone
(PCL), poly-l-lactic acid (PLLA), Profhilo®,
polymethyl-methacrylate (PMMA), lipofilling,
platelet-rich plasma and stem cell therapies is
lacking. Generally, the literature evaluated shows
that there is a need for larger, multicentre RCTs
with histological studies to confirm results relating
to all areas of the face. Currently, CaHA treatment
is consensus-led (Sundaram and Emer, 2013) and
Ellansé® is a manufacturer-led protocol (Moers-
Carpi and Sherwood, 2013). Evidence for PCL soft
tissue facial fillers has not yet been presented in the
style of a systematic review.
Conclusions
Studies continue to show that PCL and CaHA are
safe and effective. CaHa with lidocaine is shown
to be less painful than CaHA alone. Furthermore,
studies prove that CaHA and PCL lasts longer
than an equivalent HA filler (Yutskovskaya et al,
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Table 1. Results of the literature search
Author, date and country
Vallejo et al, 2018. Spain
Bertucci et al, 2017. US
Schacter et al, 2017. US
Yutskovskaya et al, 2014. Russia
Jeong et al, 2019. South Korea
Galadari et al, 2015. UAE
Moers-Carpi and Sherwood,
2013. US
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Study
Comparing efficacy and costs
of four facial fillers: Sculptra®
(poly-l-lactic acid), Radiesse®
(calcium hydroxylapatite [CaHA]),
Aquamid® (polyacrylamide) and
autologous fat in HIV-associated
lipodystrophy. Twenty-four-month
study of 147 patients
Randomised study
Multi-centre, randomised, double-
blind split-face study to evaluate
pain in nasolabial folds using new
formulation of CaHA and 0.3%
lidocaine in 102 participants
Randomised, split-face,
histomorphological study.
Radiesse (CaHA) versus
VOLUMA (HA)
A randomised, patient/evaluator-
blinded, split-face study to compare
the efficacy and safety of PCL
and polynucleotide fillers in the
correction of crow’s feet
Randomised, prospective,
blinded, split-face, single-centre
study comparing PCL to HA filler
for nasolabial fold treatment in
45 patients
Prospective, 24-month RCT
using two different formulas of
PCL-based dermal fillers to treat
nasolabial folds. (Ellansé-S and
Ellansé-M) in 40 participants
Key outcomes
Despite the nonsignificant
differences observed in the
number of sessions and
volume, autologous fat showed
significantly lower costs than all
synthetic fillers (p < 0.05).
Permanent fillers and autologous
fat achieve the most consistent
results over time, with lipofilling
being the most cost-effective
procedure
Merz Jawline Grading Score
found appropriate tool sensitive
to calcium hydroxylapatite
treatment in concordance with
aesthetic outcomes using Global
Aesthetic Improvement Score
(GAIS) and FACE-Q
CaHA with integral lidocaine
significantly reduces pain and is as
effective as CaHA
At 4 months, collagen type III
was greater with CaHA versus HA
(P=0.0052). By 9 months, type I
staining was higher with CaHA
versus HA (P=0.0135), whereas
type III was lower with CaHA
than HA (P=0.0019). Staining for
elastin, Ki-67 and angiogenesis
was greatest with CaHA at
both timepoints
No significant difference in Crow’s
Feet Grading Scale, GAIS or Ra
value on either side treated;
however results show efficacy and
safety achieved
Used Wrinkle Severity Grading
Score (WSRS) and GAIS to compare
safety, efficacy and duration. PCL
showed statistically significant
improvements on both scales,
suggesting that PCL-based dermal
fillers last longer
Used WSRS and GAIS. Ellansé-M
lasts longer. Both are safe
and effective
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Study weaknesses
• Polycaprolactone (PCL) and
hyaluronic acid (HA) were not
included in the study
• Randomised controlled trials
(RCTs) blinded with placebo are
needed to confirm results
• Bias: Merz funded the study
• Short: only evaluated once
post-procedure
• Small: only 29 participants
• No comparison to other filler with
or without lidocaine
• Only the nasolabial fold area
was explored
• Small study (only 24
participants)
• Only women
• Narrow age bracket (35–45
years old)
• Novel study, first of its kind
• Need larger scale
multicentre RCTs
• Need histological studies to
confirm the results
• Prospective
• Single-centred
• Small numbers
• Need larger scale
multicentre RCTs
• Only nasolabial folds treated
• No histological data to
confirm results
• Small numbers
© 2020 MA Healthcare Ltd
• Need multicentre RCTs
• Need histological studies
to confirm
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Key points
„ Not all skin fillers are the same, and it is
important to understand the difference
between the varieties and their effects on
the skin
„ Calcium hydroxylapatite spheres are
composed of calcium and phosphate ions
that occur naturally in human tissue and
are bioresorbable
„ Polycaprolactone is a bioresorbable soft
medical material used in Ellanse fillers and
other medical devices, such as biodegradable
sutures and orthopaedic implants
„ Studies have shown that calcium
hydroxylapatite and polycaprolactone last
longer than hyaluronic acid fillers and have
an excellent safety profile with minimal
side effects
„ Calcium hydroxylapatite and polycaprolactone
fillers cannot be dissolved with hyaluronidase
like hyaluronic acid fillers. Neither are
indicated for use in the lips.
2014; Galadari et al, 2015), and in the long term,
stimulates more type I collagen than HA fillers,
compared with Aquamid® and lipofilling (Vallejo et
al, 2018). However CaHa and PCL are irreversible
compared to HA fillers, which could be viewed as
a barrier to patient safety. Neither are appropriate
for use in the lips (Sundaram and Emer, 2013).
Only one study exists in the literature regarding
dissolving Ellansé® with methotrexate (Philibert
et al, 2020). Nevertheless, CaHA and HA fillers
should be complementary to each other, rather than
competitive (Sundaram and Emer, 2013). Lipofilling
was shown to be more cost-effective than CaHA
(Vallejo et al, 2018), though, again, this needs to be
confirmed with larger scale studies.
References
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study to detect the sensitivity of the Merz Jawline Grading
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polymer has become an innovative collagen-stimulator in
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Fakhre GP, Perdikis G, Shaddix KK, Terkonda SP, Waldorf
JC. An evaluation of calcium hydroxylapatite for cosmetic
© 2020 MA Healthcare Ltd
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Galadari H, van Abel D, Al Nuami F, Al Faresi F. A
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study comparing polycaprolactone to hyaluronic acid for
treatment of nasolabial folds. J Cosmet Dermatol. 2015;
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CPD reflective questions
„ What type of filler family do calcium hydroxylapatite and
polycaprolactone fillers belong to?
„ Explain the mechanisms by which these agents rejuvenate the skin?
„ Name two differences between calcium hydroxylapatite fillers and
hyaluronic acid fillers
„ Name two differences between polycaprolactone fillers and hyaluronic
acid fillers
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