Why Do Rejuran and Re2O Leave Bumps — and Should They?

Summary in Three Lines

• A bump is the dermis swelling as it takes up the product. The dermis is a sponge-like mesh that takes up fluid by expanding, so product held in the dermis has to swell it, and pain comes with that stretching. The pain can be eased through injection speed, the amount given at each point and anesthesia.
• Placing the product beneath the dermis is a different route. One study found that Rejuran placed beneath the dermis was not inferior to intradermal injection up to week 12, but the follow-up was short and the study was supported by the manufacturer. There is no injection that avoids both bumps and pain while placing all of the product in the dermis.
• Bump size is planned to suit the product. Dr. Jeong plans larger bumps for liquid Rejuran and small, closely spaced bumps for particulate Re2O. We have not yet found a study comparing bump size directly with results, so this is a judgment drawn from underlying principles. The injection method is chosen after first deciding where the product needs to work.

A Bump Is the Dermis Swelling as It Takes Up the Product

The Dermis Is a Sponge-Like Mesh That Holds Water

The dermis is not a solid block. Collagen and elastin fibers form a dense mesh, and the spaces between them are filled with water and hyaluronic acid. Engineers call tissue like this a "porous elastic medium": it is full of pores, and it shrinks when pressed and springs back afterward. Put simply, it is like a water-soaked sponge held inside a mesh bag.

In one experiment, water was injected through a hollow microneedle into excised pig skin while the inside of the dermis was watched in real time with optical coherence tomography (Shrestha 2018). Rather than forming a single pocket of fluid in the middle, the dermis took up the water by swelling locally in the surrounding tissue. The volume of the swelling closely matched the volume of water injected, and when the tissue was prevented from swelling, less water went in. In the same experiment, applying pressure with the needle in place did not push any water in at first; only when the needle was drawn back very slightly did the water begin to flow. The mesh compressed by the needle tip blocks the way and holds firm, and once that resistance gives, it opens and begins to swell.

In other words, the dermis is less like a container that leaks when it overflows and more like a sponge that holds firm, then opens, swells and takes the fluid in.

A Bump Is the Trace of the Dermis Taking Up the Product

In a non-randomized experiment in which saline was injected into the forearms of 10 healthy adults at different depths and speeds, every site injected at the depth of the dermis rose into a raised wheal, and only the sites injected at the depth of the fat beneath the skin did not (Gupta 2011). On ultrasound, too, the dermis at the intradermal sites had thickened and the surface had rounded upward, while the sites injected beneath the skin showed no such change.

A recent Rejuran study shows the same picture. When the product was injected into the dermis on one cheek and beneath the dermis on the other, bumps formed only on the intradermal side (Bae 2026, split-face study, 37 participants analyzed). A bump is the sign, visible from the outside, that the product has gone into the dermis.

If the Skin Did Not Swell, Where Did the Product Go?

If the same amount was injected but the skin did not swell, the product the sponge did not take up must be somewhere else.

• The skin surface — product pushed back out through the needle hole or left on the surface
• Inside the device — product that pools in the empty space inside an injector tip (covered in more detail under "Machine and Needle-Free Injection" below)
• The fat layer — product that seeps into the loose fat beneath the dermis and spreads out

From the dermis's point of view, all three are losses. Product that goes into the fat spreads out widely without forming bumps, so the surface stays smooth and the injection hurts less. A smooth surface does not mean the product went evenly into the dermis.

Conversely, a visible bump does not mean that all of the product stayed in the dermis. In a study comparing the two sides of the face in 4 people, the authors explained from their ultrasound findings that even when the needle is aimed inside the dermis, some of the product can slip just beneath it in areas where the skin moves easily (Kim 2026). A bump is evidence that product went in, not that all of it did.

Pain Is the Price of the Dermis Opening Up — It Cannot Be Avoided, but It Can Be Eased

The saying that "Rejuran has to hurt to go in properly" is half right. For the sponge-like mesh to swell, its openings have to widen, and pain comes with the stretching and opening of the dermis.

Looking again at the forearm experiment, small volumes went in at low pressure and caused very little pain. As the volume grew and the speed increased, pressure and pain rose together, and when close to 1 mL was injected at a fast rate, most participants felt a sharp, piercing pain toward the end (Gupta 2011). Pressure and pain did not always move together, however: when the needle was drawn back slightly before injecting, the pressure was lower but the injection hurt more. And because this experiment used saline, the picture may differ with the product actually injected.

Rejuran research points the same way. Pain scores were higher at every session on the side injected into the dermis than on the side injected beneath it (Bae 2026). In a randomized split-face study of enlarged pores, pain scores were also higher on the side injected into the dermis with a needle than on the side laid beneath the dermis with a cannula (Chinpipat 2026, 30 participants). Pain is less a sign that the product "went in well" and more the price paid as the dermis opens up.

Ways to Ease the Pain

• Speed — pushing slowly means less pressure builds up, and less pain, for the same volume (Gupta 2011).
• Amount per point — setting the amount delivered at each point to suit the product keeps pressure from building up all at once.
• Anesthesia and cooling — the injection technique stays the same and the anesthesia is reinforced. We use Cooling Anesthesia: an anesthetic cream containing vasoconstricting and cooling ingredients, followed by cold-air cooling. It does not take the pain away entirely, but it can help reduce the discomfort.
• Formulation — in a randomized split-face study, a PN formulation with adjusted acidity and ionic strength produced lower pain scores than the conventional formulation (Jeon 2026, 15 participants, crow's feet).

Ways of managing procedural pain more broadly are covered in our article on pain in dermatologic procedures. Product cannot be placed in the dermis without opening it up, but there are ways to open it up with less pain.

Larger Bumps for Liquid Products — The Signal a Stretched Dermis Sends to Fibroblasts

Here we start with the research and then turn to the principle. In a study in which a cross-linked hyaluronic acid filler and saline were each injected into photoaged forearm skin (11 people, mean age 74) and the tissue was examined 4 and 13 weeks later, new collagen had built up around the filler, and the fibroblasts looked elongated, as if they had been pulled (Wang 2007). The authors interpreted this as the fibroblasts being stretched and activated as the dermis was stretched: as the mesh was pulled, the cells attached to it were pulled too.

Another study looked at this process more closely in the skin of people over 70. When the dermal mesh was given support with filler, the fibroblasts spread out and elongated, and the signals that drive collagen production (the TGF-β receptor and CTGF) increased (Quan 2013). Even aged fibroblasts go back to work once they have a mesh to grip and pull against. This conversion of the force of stretching tissue into signals inside the cell is called mechanotransduction.

There are also reports that saline alone can leave a similar trace. In a comparison study, the control site where saline was injected into the skin below the ear also showed a higher collagen staining measure 28 days later than before treatment (Abuaf 2016, non-randomized controlled study, 20 women in their 40s). This result mixes the effects of needle stimulation and swelling, however, so it cannot say which of the two was responsible.

Dr. Jeong's Judgment — Still an Inference Drawn from Principle

These studies used cross-linked hyaluronic acid, which holds the space open for weeks, and were done in areas other than the face, such as the forearm. They cannot be carried over as they stand to Rejuran bumps, which settle far sooner. Even so, Dr. Jeong plans larger bumps for liquid products such as Rejuran, for two reasons.

• Stretch — he judges that the more widely the mesh is pulled, the stronger the mechanical signal the fibroblasts receive is likely to be.
• Residence time — the dermis is dense, so he judges that product held in a larger volume at one spot stays there and gains more time to work.

We have not yet found a clinical study directly comparing bump size with results, so this point is Dr. Jeong's judgment, drawn from the principles in the studies above.

Studies of Injection Beneath the Dermis — The Counter-Evidence and Two Different Routes

There is evidence pointing the other way, too. In a prospective split-face study, a zone from under the eye to the front of the cheek was marked out, and Rejuran was injected at multiple points into the dermis of the left cheek and laid beneath the dermis of the right cheek with a cannula (Bae 2026; 40 people treated, 37 analyzed; 3 sessions at 3-week intervals). At week 12, the side treated beneath the dermis was not inferior to the intradermal side on a fine-line measure; its pain scores were lower at every session, and no bumps formed.

A few limitations need to be read alongside this study.

• Follow-up went only to week 12. The authors themselves wrote that injection depth may affect how the product spreads and how long it stays in the tissue, so longer follow-up is needed.
• The sides were not randomly assigned: every participant received intradermal injection on the left and injection beneath the dermis on the right.
• The study was supported by the manufacturer.

A study of enlarged pores (Chinpipat 2026, randomized split-face study, 30 participants) shows a somewhat different picture. On the side injected into the dermis with a needle, pore volume decreased significantly from month 3; on the side laid beneath the dermis with a cannula, it decreased to a similar level by months 4 to 5. There was no significant difference between the two techniques; pain scores were higher on the needle side, and minor side effects were also reported more often there.

A formulation study is also worth noting. A PN formulation with adjusted acidity and ionic strength produced bumps less often than the conventional formulation, yet the improvement in crow's feet was similar (Jeon 2026). This suggests that results are possible even with small bumps, a reminder that Dr. Jeong's "larger bumps for liquid products" is still an inference.

Why the Skin Can Still Improve — Dr. Jeong's Interpretation

Dr. Jeong thinks there is a second route besides working within the dermis. Liquid PN dissolves and spreads, so even when it is laid just beneath the dermis, its signals may reach the dermis above. For a particulate product such as Re2O, he thinks that a layer beneath the dermis may form a mesh-like support (a scaffold) that holds the tissue above it and gives the skin a firmer feel.

Compared with injecting directly into the dermis to aim for the stretch and the longer residence time as well, however, there may be less to gain. The skin can improve with injection beneath the dermis, but that does not replace keeping the product within the dermis; it is a different route. Keeping product in the dermis still means swelling it, and the price is bumps and pain. Which route to take is decided by weighing the result you want against the pain you are willing to accept.

Re2O in Small, Closely Spaced Bumps — A Sponge Soaks Up the Water but Leaves the Grains

Re2O is a particulate skin booster made by finely processing matrix taken from human dermis with the cells removed (hADM). In a randomized, split-face, double-blind study, measures of skin density, elasticity, wrinkle depth, pores and hydration differed between the Re2O side and the hyaluronic acid control side (Lee 2026, 20 people, 20 weeks). One of the authors had served as an adviser in developing the product, and we note that here as well.

Even so, Dr. Jeong thinks it behaves differently in the dermis from liquid Rejuran. Pour water containing grains onto a sponge, and the water is drawn into the sponge's pores and spreads, while grains larger than the pores are filtered out and stay where they were poured. He thinks the dermis behaves in a similar way: the liquid spreads through the mesh, while the particles gather and stay at the injection site. So if Re2O is given as one large bump at a single point, that bump becomes a "clump of grains" that remains after the fluid has drained away, lasting longer and sometimes being palpable. That said, one experiment found that a single 0.1 mL injection into excised human skin spread evenly within the dermis (Lee 2026), so it cannot be said to clump every time.

"Small and Closely Spaced," Seen from the Cell Side

In the same study's rat experiment, new collagen formed more at the edges of the injected matrix, the boundary where it meets the surrounding tissue, than at its center (Lee 2026, animal study). In a study of different materials, in which biologically derived matrices were implanted in the rat abdominal wall, the tissue was rebuilt more constructively where there were more healing-type (M2) macrophages at 2 weeks (Brown 2012, animal study). Broadly, M1 macrophages drive inflammation, while M2 macrophages clear up and rebuild. The Re2O material itself also reduced inflammatory substances released by activated macrophages in the laboratory (Lee 2026, cell study).

For the same volume, several small bumps have a far larger boundary with the surrounding tissue than one large bump, and Dr. Jeong thinks this gives macrophages and fibroblasts more room to work.

Even a Short Needle Depends on Depth

Even a short needle 2 mm long, if pushed straight in to its full length, can easily take its tip below the dermis. In a study that measured living faces by ultrasound, the full thickness of the skin over the cheekbone averaged 1.49 mm, of which the dermis averaged 1.16 mm (Jeong 2023). A network of blood vessels runs horizontally along the border between the dermis and the fat beneath it (Braverman 1997), so when the needle tip reaches this border, bruising is more likely, and the product tends to escape into the fat, where resistance is lower. Strictly speaking, this too is a loss from the dermis's point of view. The problem is not the short needle itself but assuming that a short needle must be shallow and pushing it straight in all the way.

More about Re2O is covered in our article comparing GOURI and Re2O.

Machine and Needle-Free Injection — Depth Settings and the Thickness of Living Skin

When the Needles on a Negative-Pressure Multi-Needle Injector Are Set Short

Here we look at the physics of one setting in particular: shortening the needles in order to avoid bumps and reduce pain. A negative-pressure multi-needle injector is a device whose tip is pressed against the skin, draws the skin up slightly by suction, and then delivers the product through several needles at once. Because the needle length can be adjusted, the needles are sometimes set short to reduce bumps and pain. But setting the needles short creates places where the product can escape.

• The bevel — if part of the slanted face of the needle tip sits outside the skin or inside the tip, the product exits toward the tip rather than into the skin.
• Empty space inside the tip — the shorter the needles are set, the further they draw back into the tip and the larger the empty space becomes, and that space holds product.

Product left in the device or on the surface can be measured, but weighing cannot tell whether the product that went into the skin stayed in the dermis or slipped beneath it. The clue to that difference, visible from the outside, is the bump.

In a randomized study that used the same type of negative-pressure injector with the needles set deep, aiming the Re2O at the mid-dermis, an effect was confirmed (Lee 2026). In other words, the depth setting matters more than the device. Setting the needles long enough brings bumps and reduces leakage, but the pain comes back with them; gaining one thing means giving up another. If no bumps formed yet all of the product was used, it is worth asking once where that product went.

"The Skin Is Too Thin to Reach the Dermis with a Needle"? — Cadaver Skin and Living Skin

One argument holds that if you draw the dermis and a needle to the same scale, the dermis looks so thin that a needle cannot place product accurately in it and most of it ends up in the fat, which leads to the conclusion that only a needle-free jet injector can deliver into the dermis. Dr. Jeong sees it somewhat differently, for three reasons.

• The thickness in the drawing — cadaver tissue loses water and shrinks, so it can differ from the real thickness. In a study that measured 8 sites on the faces of 99 living Korean adults by ultrasound (Dr. Jeong is its first author), the average full skin thickness was 1.31 mm at the outer forehead, 1.49 mm over the cheekbone and 1.64 mm at the corner of the mouth (Jeong 2023). A 34G needle has an outer diameter of 0.18 mm (ISO 9626:2016), so the dermis over the cheekbone (average 1.16 mm) is about six times as thick as the needle. Inserted at a shallow angle with the bevel facing up, the needle tip can stay well within the dermis.
• The dermis is a sponge, not a cup — the picture in which injecting more than the dermis's thickness makes it overflow treats the dermis as a rigid cup. As we saw above, the dermis takes product in by swelling, and that swollen spot is the bump. The authors of the forearm experiment also interpreted their findings as showing that a single dermal site swelled to take up around 0.5 mL of saline before the pressure rose steeply (Gupta 2011).
• Jets swell the dermis too — on the side treated with PN using a needle-free device that sprays the product with cryogenic cooling, the authors described multiple small pockets forming in the upper and middle dermis on ultrasound (Kim 2026, 4 participants). The study compared results and pain with hand injection, but with only 4 participants it is for reference only at this stage.

The last point matters in particular. Even when product is delivered without a needle in very small amounts, whatever enters the dermis swells that spot. It may not be a visible bump, but it shows on ultrasound. Whatever the method, if the dermis did not swell at all, it is worth considering that the product may be outside the dermis.

It is true, though, that if the needle tip sits on the border between the dermis and the fat, product leaks toward the fat, where resistance is lower; the ultrasound observations above (Kim 2026) say the same. That is why the needle should go in shallow and at an angle, with each point receiving only as much as that spot can hold. Needle-free injectors, for their part, reach different depths depending on the pressure. In a study that injected into cadaver cheeks with a needle-free injector, the depth and shape of penetration changed with the pressure, and in some cases the product passed through the dermis to reach the fascial layer (Seok 2016).

We also use a needle-free injector (Synerjet), mainly for scar treatment or to deliver product after several lasers have opened pathways for it. Each device has the situations it suits.

The Injection Method Is Chosen to Suit Where the Product Needs to Work

With hand injection, the depth, angle and amount can be adjusted point by point by feel. So we use hand injection when bump size needs to be designed differently for each product, larger for Rejuran and small and closely spaced for Re2O, and when product needs to be placed evenly over curved areas.

Machine injection suits other situations. For products such as Juvelook, where dividing the product into very fine portions is itself a safety measure, machine injection is a good fit, and for patients who are very worried about pain, we also offer the X-Injector, a machine injector, as an option. We decide on the method together after weighing pain, results and leakage. How hand and machine injection differ in delivery is explained in our article on skin booster delivery.

The planning order is this: rather than choosing the injection method first, we decide where the product needs to work, and then choose the bump size and the injection method (cannula, hand injection, machine injection or a needle-free injector).

In Summary — No Injection Avoids Bumps and Pain While Placing Everything in the Dermis

• For product to work in the dermis, the dermis has to swell, and pain comes with the swelling.
• There are techniques to ease the pain, but there is no way for product to stay in the dermis without swelling it.
• Injection beneath the dermis can also be a good route. But it is a different route, and it does not do exactly what keeping product in the dermis does.

So rather than asking "Will it hurt?", we suggest asking first "Where does this product need to work, and what am I willing to give up for that?" The product, the bump size and the injection method are decided together with your current skin concerns and how much the pain worries you.

Precautions and Limits of the Evidence

Bump size, pain and results can vary with an individual's skin thickness and elasticity and with the area treated. After skin booster injections, bruising, swelling, temporary redness and bumps can occur, and with particulate products, nodules or a foreign-body sensation can, rarely, persist for a long time. If symptoms last or get worse, please consult the medical team that treated you.

This article is general information based on research and public information published to date, and does not replace individual medical care. The relationship between bump size and results includes Dr. Jeong's judgment, as no study directly comparing the two has been found. Many of the studies cited were small, or were done under conditions different from facial skin boosters, such as in the forearm, in cadavers, in animals or in cells.

References

1. Shrestha P, Stoeber B. Fluid absorption by skin tissue during intradermal injections through hollow microneedles. Sci Rep. 2018;8(1):13749. doi:10.1038/s41598-018-32026-9
2. Gupta J, Park SS, Bondy B, et al. Infusion pressure and pain during microneedle injection into skin of human subjects. Biomaterials. 2011;32(28):6823-6831. doi:10.1016/j.biomaterials.2011.05.061
3. Bae H, Kim SB, Heo YR, et al. Efficacy and safety of intradermal versus subdermal injection of polynucleotide for facial improvement: a prospective split-face study. J Cosmet Dermatol. 2026;25(8):e71108. doi:10.1111/jocd.71108
4. Kim M, Suwanchinda A, Kim JH, et al. Supersonic cryogenic jet delivery of polynucleotides compared with manual intradermal injection. Plast Reconstr Surg Glob Open. 2026;14(2):e7509. doi:10.1097/GOX.0000000000007509
5. Chinpipat P, Chirasuthat S, Boonpethkaew S, et al. Polynucleotide injection for enlarged pores: comparison of intradermal needle and subdermal cannula techniques in a randomized split-face trial. J Cosmet Dermatol. 2026;25(6):e70946. doi:10.1111/jocd.70946
6. Jeon W, Park M, Kim SW, Kim J. Efficacy of ionization-adjusted PN filler in minimizing injection pain: a randomized, patient-blinded, split-face study. Aesthetic Plast Surg. 2026;50(7):2723-2730. doi:10.1007/s00266-025-05320-x
7. Wang F, Garza LA, Kang S, et al. In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin. Arch Dermatol. 2007;143(2):155-163. doi:10.1001/archderm.143.2.155
8. Quan T, Wang F, Shao Y, et al. Enhancing structural support of the dermal microenvironment activates fibroblasts, endothelial cells, and keratinocytes in aged human skin in vivo. J Invest Dermatol. 2013;133(3):658-667. doi:10.1038/jid.2012.364
9. Abuaf OK, Yildiz H, Baloglu H, et al. Histologic evidence of new collagen formulation using platelet rich plasma in skin rejuvenation: a prospective controlled clinical study. Ann Dermatol. 2016;28(6):718-724. doi:10.5021/ad.2016.28.6.718
10. Lee YI, Chau NH, Nguyen NH, et al. Injectable particulated human acellular dermal matrix booster for skin restoration: an integrated randomized, split-face, double-blinded clinical trial and preclinical study. Int J Mol Sci. 2026;27(5):2193. doi:10.3390/ijms27052193
11. Brown BN, Londono R, Tottey S, et al. Macrophage phenotype as a predictor of constructive remodeling following the implantation of biologically derived surgical mesh materials. Acta Biomater. 2012;8(3):978-987. doi:10.1016/j.actbio.2011.11.031
12. Jeong KM, Seo JY, Kim A, et al. Ultrasonographic analysis of facial skin thickness in relation to age, site, sex, and body mass index. Skin Res Technol. 2023;29(8):e13426. doi:10.1111/srt.13426
13. Braverman IM. The cutaneous microcirculation: ultrastructure and microanatomical organization. Microcirculation. 1997;4(3):329-340. doi:10.3109/10739689709146797
14. Seok J, Oh CT, Kwon HJ, et al. Investigating skin penetration depth and shape following needle-free injection at different pressures: a cadaveric study. Lasers Surg Med. 2016;48(6):624-628. doi:10.1002/lsm.22517
15. ISO 9626:2016. Stainless steel needle tubing for the manufacture of medical devices — Requirements and test methods. Geneva: International Organization for Standardization; 2016.

From Consultation Through Treatment

A board-certified dermatologist examines you directly, identifies which layer the cause sits in, sets the device and the parameters, and then carries out the procedure as the same physician. This is not a structure in which a consultant sells the treatment.

The number of sessions, the intervals, the maintenance point and the cost are agreed together before the first session.

Related care: Rejuran Healer Salmon DNA Regeneration · Skin Booster Rejuvenation Treatment in Seoul