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Received: 17 November 2021 | Revised: 26 April 2022 | Accepted: 17 May 2022

DOI: 10.1111/jocd.15101

LETTERS TO THE EDITOR

Retaining even distribution of biostimulators microscopically

and grossly: Key to prevent non-­inflammatory nodules
formation

To the Editor, micro-­clumps may cause needle clogs, which leads to technical er-
Over the past decade, biostimulators have become increasingly rors such as uneven distribution of the product when injected, and
popular for soft tissue contouring and volumizing. Although the results in nodules formation or irregularities post-­injection. Thus,
incidence rate of non-­inflammatory nodules or irregularities post-­ retaining the even distribution of product microscopically (pre-­
injection is low, treatment is difficult in the event of such adverse injection) is crucial to prevent non-­inflammatory nodules formation.
events. The causes of these adverse events are list in Table 1. We Retaining the even distribution of product grossly (post-­
can conclude that they are related to one root cause: the uneven injection) is also crucial to prevent irregularities or non-­inflammatory
distribution of the product, either microscopically (pre-­injection) or nodules formation. Technical errors when injecting is a major cause
grossly (post-­injection). of aggregation or uneven distribution of the product.1–­3 Therefore,
Currently, there are 4 biostimulators available on the market practitioners should be highly proficient at injection techniques. In
as follows: poly-­L-­lactic acid (PLLA; Sculptra; Galderma),1 calcium the serial puncture injection technique, injecting a small amount of
hydroxylapatite (CaHA; Radiesse; Merz), 2 polycaprolactone (PCL; product per bolus is recommended. In the retrograde or fan injection
Ellanse; Sinclair),3 and poly-­D,L-­lactic acid (PDLLA; AestheFill; technique, ensure a small amount and even distribution of the prod-
4
REGEN). All 4 of these biostimulators comprise of specific biode- uct is injected per tunnel tract.1–­3 Due to the visibility and palpability
gradable micro-­particles, which can stimulate an inflammatory re- of the product through the skin, a superficial injection is not recom-
sponse and collagen neogenesis to achieve volume restoration.1–­4 mended, except for hyper-­diluted products.6 However, when deeply
Both injectable PLLA and PDLLA are supplied as lyophilized injecting these products, care must be taken to not inadvertently
powder. Prior to injection, reconstitution with sterile water for injec- inject into the muscles of hyper-­dynamic regions such as peri-­orbital,
tion (SWFI) is required.1,4 However, injectable PLLA tends to form glabella, and peri-­oral regions; and certain confined regions such as
dry PLLA micro-­clumps in the suspension after reconstitution with orbital post-­septal compartments, gland tissues, and fascial/tendi-
SWFI. The presence of dry PLLA micro-­clumps is a risk factor for the nous layers. Due to contractions, injecting products into muscles will
1,5
formation of papules and nodules several weeks after injection. cause product aggregation and result in nodules formation. Injecting
In injectable PDLLA, micro-­clumps formation seldom occurs when products into certain confined regions will restrict even distribution
SWFI is used for reconstitution. However, it occurs when normal and cause product aggregation, which result in nodules formation.1–­3
4
saline is used. In injectable PCL and CaHA, micro-­clumps forma- For injectors who are less adept at these techniques or for super-
6
tion may occur when the dilution method is administered. These ficial placement of the products, using hyper-­diluted products is a

TA B L E 1 Causes of nodules formation after biostimulators injection

Inflammatory nodules Non-­inflammatory nodules

General causes2 General causes (technical mishaps)1–­3

• Infection • Injection too quickly
• Biofilm • Injection of large volumes of highly concentrated product
• Type IV hypersensitivity reaction • Migration (dislocation) of filler material
• Granulomatous reaction • Injection too superficially
• (Pseudo)abscess • Contour irregularities
• Injection into locations that are not optimally chosen vis-­à-­vis its mechanism of action (dermis, muscles,
lips, eyelids, etc.)
Filler-­specific causes
• PLLA1,5: dry PLLA micro-­clumps formation after reconstitution with SWFI; inadequate reconstitution
volumes; short hydration times; shake the vial during hydrationtable
• PDLLA4: PDLLA micro-­clumps formation after reconstitution with NS

Abbreviations: NS, normal saline; PDLLA, poly-­D,L-­lactic acid; PLLA, poly-­L-­lactic acid; SWFI, sterile water for injection.

J Cosmet Dermatol. 2022;00:1–3. wileyonlinelibrary.com/journal/jocd© 2022 Wiley Periodicals LLC. | 1

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2 LETTERS TO THE EDITOR

TA B L E 2 Causes, solutions, and key of solutions related to non-­inflammatory nodules or irregularities of biostimulators

Step of
procedure Causes Solutions Key of solutions

Reconstitution/ Dry PLLA micro-­clumps formation Increase the reconstitution SWFI amount Retaining product micro-­particles
Dilution after reconstitution of injectable to 7–­8 ml; lengthen the reconstitution evenly distributed microscopically
PLLA with SWFI (It may directly time to ≥24 h; do not shake the vial in suspension before injection
cause papules and/or nodules during hydration; massage the inject
formation after injection; or it site after injection.1,5,6
may cause technical errors while
injection due to needle clogs.)1,5,6
PDLLA micro-­clumps formation Use SWFI for reconstitution of injectable
after reconstitution of injectable PDLLA; with NS, use the Back-­and-­
PDLLA with NS (It may cause Forth method for reconstitution of
technical errors while injection injectable PDLLA.4
due to needle clogs.) 4
PCL or CaHA micro-­clumps formation Use the Back-­and-­Forth method for
after dilution with NS (It may thoroughly dilution of injectable PCL
cause technical errors while and CaHA
injection due to needle clogs.)6
Injecting Injecting biostimulators into Avoid injecting biostimulators into Retaining injected product evenly
muscles of “dynamic” facial “dynamic” facial areas; in glabella distributed grossly in treated areas
areas, such as lips, glabella, region, inject biostimulators 1 week after injection
and peri-­orbital regions (It may after injection of botulinum toxin;
cause product aggregation and in peri-­orbital regions, inject diluted
nodules formation due to muscle biostimulators into subcutaneous layer
contractions.)1–­3 with even distribution
Injecting biostimulators into confined Avoid injecting biostimulators into these
regions (dermis, glands, fascia, regions; inject diluted biostimulators
ligaments, tendons, orbital post-­ into subcutaneous layer with even
septal compartments, etc) distribution; injectbiostimulators into
(It may limit even distribution of supra-­periosteum layer with small
the product and cause nodules volume per single dot
formation.)1
Other technical errors such as Avoid injecting too much amount of
injection too quickly, inadvertently biostimulators (of thick biostimulators,
placement too much amount of no more than 0.2 ml) in a single dot;
biostimulators in a single dot, evenly distribute the suspension;
and/or uneven distribution of be familiar with all the injection
biostimulators techniques; do not inject too
(It may cause product migration, and superficially; inject thinner or diluted
various-­size nodules formation or biostimulators.1–­4
irregularities.)1–­4

Abbreviations: CaHA, calcium hydroxylapatite; NS, normal saline; PCL, polycaprolactone; PDLLA, poly-­D,L-­lactic acid; PLLA, poly-­L-­lactic acid; SWFI,
sterile water for injection.

preferred method of choice. As the dilution reduces pressure on the most cases, non-­inflammatory nodules can resolve spontaneously. 2
plunger, it eases filler delivery for the injector and facilitates even Therefore, for deep-­located or invisible nodules, regularly follow-­up
distribution.6 For further details of the causes and solutions related is another choice.
to non-­inflammatory nodules and irregularities of biostimulators, In conclusion, retaining an even distribution of biostimulators
see Table 2. both microscopically (pre-­injection) and grossly (post-­injection) is
In the management of non-­inflammatory nodules, intralesional crucial to prevent non-­inflammatory nodules formation and other
injection of sterile water, prednisolone, or triamcinolone, with mas- irregularities. However, several factors may affect the final injection
saging might be helpful. 2,3 For superficial or visible nodules, injecting result, as each type of biostimulator has its own unique properties.
hyaluronic acid around these nodules as camouflage is an alternative Thus, practitioners who intend to administer these products must
method. Excision should be avoided unless the surgical wound can be knowledgeable of the potential risks and the management of the
be concealed, such as sub-­ciliary incisions for lower eyelid nodules. In adverse effects.
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LETTERS TO THE EDITOR 3

AC K N OW L E D G E M E N T Correspondence
The authors specially thank Louise Cheng and Sasa Chen for their Chuan-­Yuan Lin, Li-­An Medical Clinic, 4F., No. 267, Lequn
kind assistance with manuscript editing. 2nd Road., Zhongshan District, Taipei City 104452, Taiwan.
Email: [email protected]
C O N FL I C T O F I N T E R E S T
Dr. Hsu N-­J is a speaker and consultant for Galderma. Dr. Lin J-­Y and ORCID
Dr. Lin C-­Y are medical directors of REGEN Biotech. Chuan-­Yuan Lin https://orcid.org/0000-0003-2306-478X

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