Does injecting small amounts of fillers prevent the development of secondary blindness?

Inadvertent entry of filler products into the supratrochlear, supraorbital, or dorsal nasal arteries, among other branches of the ophthalmic artery, might result in an immediate and devastating loss of vision. We wanted to examine how much filler could block the ophthalmic artery.

The number of documented ocular problems has increased with the increase in demand for filler injections.Fifty ocular problems due to filler injections without fat grafts have been documented until 2018. 4This number is probably underreported, as only published cases were counted; there may be several more cases in clinical practice that are yet to be reported.
The supratrochlear, supraorbital, and dorsal nasal arteries, which are branches of the internal carotid artery, are located in the glabella and nose, where injections resulting in blindness are most frequently administered.The external carotid artery feeds the supratrochlear, supraorbital, and dorsal nasal arteries via the ophthalmic artery and also gives rise to the superficial temporal, infraorbital, and facial arteries, which are crucial blood vessels.Injecting small amounts of filler can reportedly prevent blindness.In this study, we injected a filler into each branch of the ophthalmic artery that may be responsible for the potential loss of vision.

| MATERIAL S AND ME THODS
A total of 51 ophthalmic arteries from 29 Korean cadavers (17 men and 12 women; mean age at death, 79.2; range, 61-92 years) were dissected to allow harvesting of the ophthalmic artery and its branches.After the dissection, 17 filler injections were introduced into the supratrochlear, supraorbital, and dorsal nasal arteries each.
The amount of injected filler required to block the whole ophthalmic artery was measured using a ruler.
The subcutaneous tissues of the orbital regions were dissected to reveal the origin of the ophthalmic, supratrochlear, supraorbital, dorsal nasal, central retinal, and posterior ciliary arteries.The supraorbital, supratrochlear, and dorsal nasal arteries were harvested and cut from the orbital rim, where the main trunk was located.The reason for choosing the orbital rim as the standard injection site for fillers is because injections are typically performed distal to the orbital rim.This area is anatomically stable and provides a reliable location to access the arteries, which are mostly found in a single arterial trunk.
After dissection, a polycprolactone (PCL) filler, Lafullen (Samyang Holdings Co., South Korea), for its white visible color, was injected into the supraorbital, supratrochlear, and dorsal nasal arteries, while blocking the other branches.The injection was administered and injected slowly from the distal end of the artery until it reached the origin of the ophthalmic artery.Measurements were performed using a ruler marked on the syringe (Figure 2).

| Phosphotungstic acid (PTA) staining
The obtained head specimens were fixed by treating with 10% normal buffered formalin for 4 days, followed by a dehydration with increasing concentrations of ethanol from 30%-70% over the subsequent 3 days.Then the tissues were stained with 1% PTA solution in 70% ethanol and placed on a shaker at 60 rpm for 10 days.A 10% PTA (Phosphotungstic Acid) stock solution was prepared utilizing phosphotungstic acid powder (~70%) sourced from Daejung, South Korea (Catalog number: 6539-4125).This stock was subsequently diluted in 99% ethanol to generate a 1% PTA solution in a 70% ethanol medium.

| Micro-Computed tomography and computed tomography
The scanning parameters of micro CT for human soft tissue was analyzed by the Nano & Microfocus X-ray computed tomography The backflow of the filler embolus from the supratrochlear, supraorbital, and dorsal nasal arteries into the ophthalmic artery.Thereafter, the material is pushed down by the arterial pressure into the central retinal and posterior ciliary arteries that supply the retina.This results in a retinal embolism, causing secondary blindness.system (v|tome|x m, BakerHughes) with minimum detectability of 0.2 μm, minimum voxel resolution of 0.5 μm, highest power of 300 kV/500 W, and image resolution of image pixel grid 4048 × 4048.
The ophthalmic artery with supratrochlear, supraorbital and dorsal nasal arteries were then observed for one specimen.The diameter and the length of each artery was measured using standard imaging software (ImageJ, NIH, Bethesda, MD) to determine the intravascular volume of the filler to block whole ophthalmic artery from each supratrochlear, supraorbital, and dorsal nasal arteries. 5

| Statistical analysis
Values are presented as the mean ± standard deviation.The amount of filler injected per artery was analyzed using SPSS.Comparisons among cadavers based on arteries and sex were performed using independent t-tests.Statistical significance was set at p < 0.05.
Difference between three groups were compared using one way anova method using R (version 4.0.0).

| RE SULTS
The mean filler volume injected into the supratrochlear artery was 0.0397 ± 0.010 mL.The mean filler volume injected into the supraorbital artery measured 0.0409 ± 0.00932 mL (Table 1), and the dorsal nasal artery measured 0.0368 ± 0.00732 mL.There were no significant differences between these arteries and individual demographics (p > 0.05) (Figure 3).
The micro-computed tomography of the ophthalmic artery and its branching arteries of supratrochlear, supraorbital, and dorsal nasal artery had obstructing volume of 0.0393 mL, 0.0483 mL, and 0.0371 mL, respectively (Figure 4).

| DISCUSS ION
The most serious adverse consequence of HA filler injections into numerous areas of the face, including the nasolabial, temple, cheek, and even chin augmentation, is visual loss. 2 The risk of blindness from fillers is highest in the glabella (38.8%), followed by the nasal region (25.5%), according to a review by Beleznay et al.The reverse flow of the HA filler embolus from the injected location through the vascular anastomoses is thought to be the mechanism that eventually causes opthalmic artery blockage.The glabellar and nasal regions, which are primarily supplied by the supraorbital, supratrochlear, and dorsal nasal arteries, account for the majority of the documented cases. 6merous strategies have been suggested to prevent this secondary blindness. 1,7The use of Doppler ultrasound-guided injections has been recommended as a preventive method.Additionally, the use of a cannula, rather than a needle, prevents arterial puncture.Because the essential arteries (dorsal nasal, supratrochlear, and supraorbital arteries) have a diameter of approximately 1 mm, larger diameter cannulas are typically safer than smaller diameter cannulas. 8An artery cannot be penetrated by a cannula with a relatively large diameter according to a comparison diagram between arterial diameter and cannula. 9 the study we conducted micro computed tomography to confirm the result of dissection based study, and found out there were no differences between them.The micro computed tomography method allows a three-dimensional observation with wholemount staining for contrast enhancement.A precise anatomical understanding of the anatomical structures could be analyzed and measured.Most recent morphological studies performed micro computed tomography with staining on small human samples such as the infraorbital area (e.g., anatomy of the orbicularis retaining ligament) and area of the nasolabial fold (e.g., muscular arrangement).
In the phosphotungstic acid applied micro-computed tomography study, the minuscule muscular structures of the nasolabial fold area, the original location of the orbicularis retaining ligament, and its course within the muscular and connective tissue were well distinguished because the size of the specimen was small. 10 a previous investigation, Khan and colleagues aimed to determine the minimum quantity of filler necessary to cause embolia cutis medicamentosa.The study centered on the examination of the volume of the supratrochlear artery, which spans from the glabella to the bifurcation of the ophthalmic and central retinal arteries, utilizing six recently deceased cadaver heads that underwent latex injection to render the artery visible.The outcomes of the study revealed that the vessel volumes ranged from 0.04 to 0.12 mL, with an average volume of 0.085 mL. 11However, our results differ from theirs, possibly due to differences in the methodology used, such as the TA B L E 1 The volume of filler injected from supraorbital, supratrochlear, and dorsal nasal artery to block whole ophthalmic artery.The lack of data from live humans limits this study's findings.

Number of specimen
Information on the actual arterial pressures can be used to determine whether blindness would occur in a live person.Actual ejection pressures are reportedly substantially higher than blood pressure. 13is indicates that even a tiny filler injection is sufficient to raise the opthalmic artery pressure.
Extrapolating findings from cadaver studies to living humans presents certain limitations.These studies do not consider the counteracting blood pressure that could be overcome by the pressure of injection, although this effect may differ depending on the size of the injected aliquot (small volume aliquots versus large).The hemodynamics of circulation and the deactivation of small amounts of hyaluronic acid intravascularly, which likely occurs rapidly and continuously, are also not accounted for.Additionally, it is likely that a smaller volume is needed to fill a vessel in a cadaver compared to a living individual.Again, the ethnic background of the cadaver used in previous studies could have been a factor contributing to the variation in results.
Injecting modest amounts of filler has been previously recommended by several medical professionals to prevent filler-induced blindness. 2,9In contrast to this claim, we determined that a small amount of filler was sufficient to completely block the ophthalmic artery in this study.Kyu-Ho Yi, and Hyung-Jin Lee wrote the paper.

ACK N OWLED G M ENTS
The authors sincerely thank those who donated their bodies to science so that anatomical research could be performed.Results from such research can potentially increase mankind's overall knowledge that can then improve patient care.Therefore, these donors and their families deserve our highest gratitude.

FU N D I N G I N FO R M ATI O N
This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIP) (NRF-2020R1A2B5B0100223811).

CO N FLI C T O F I NTE R E S T S TATE M E NT
I acknowledge that I have considered the conflict of interest statement included in the "Author Guidelines."I hereby certify that, to the best of my knowledge, that no aspect of my current personal or professional situation might reasonably be expected to significantly affect my views on the subject I am presenting.There is no conflict of interest for all authors including Kyu-Ho Yi, Hyung-Jin Lee, Woo-Ram Kim, Min-Ho An, Hyun-Jin Park, Hyewon Hu, and Hee-Jin Kim.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available on request from the corresponding author.The data are not publicly available due to privacy or ethical restrictions.

E TH I C S S TATEM ENT
This study was conducted in compliance with the principles set forth in the Declaration of Helsinki.Consent was received from the families of the deceased patients before beginning the dissections.

F I G U R E 4
The computed tomography to analyze each arteries to obstruct its whole ophthalmic artery.The supratrochlear, supraorbital, and dorsal nasal drains to ophthalmic artery then drains into the internal carotid artery.

F I G U R E 2
Image of a dissected ophthalmic artery with the supratrochlear, supraorbital, and dorsal nasal arteries.The filler was injected into each vessel, while blocking the other branches.| 87YI et al.

F I G U R E 3
The box plots demonstrate the volume (ml) of the filler injected in each of the supratrochlear artery (ST), supraorbital artery (SO), and dorsal nasal artery (DN) to block the ophthalmic artery.amount of latex injected, or the ethnicity of the cadavers used.It is also possible that differences in the length of the arteries measured may have contributed to the variance in results.The study of Cho et al., used a perfusion model that replicated the physiological blood pressure and flow rate of relevant arteries. 12They cannulated the superficial branch of the supratrochlear artery in six cadaver heads and injected hyaluronic acid filler mixed with methylene blue.They successfully demonstrated emboli reaching the ophthalmic artery in three out of six cadavers.The angiogram showed a cut-off sign in the ophthalmic artery due to hyaluronic acid filler emboli.The study concluded that retrograde emboli of hyaluronic acid filler could reach the ophthalmic artery by cannulating the supratrochlear artery, highlighting the superficial location of the supratrochlear artery, its rich surrounding vasculature, and anatomical variations as contributing factors.
AUTH O R CO NTR I B UTI O N S Kyu-Ho Yi, Hyung-Jin Lee and Woo-Ram Kim performed the research.Min Ho An, Hyun-Jin Park, Hyewon Hu and Hee-Jin Kim designed the research study.Kyu-Ho Yi, and Hyung-Jin Lee, contributed essential reagents or tools.Woo-Ram Kim analyzed the data.