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The Lasting Effects of Fillers through Neocollagenesis

The Lasting Effects of Fillers through Neocollagenesis

Cathy KogerEnhancement of an individual’s cosmetic appearance is ever growing in popularity within our society, which has largely driven the demand for various dermal fillers and neurotoxins. Many patients, however, express concern regarding the cost of such cosmetic modalities. Research has given insight to the fact that specifically hyaluronic acids (HAs) may provide lasting cosmetic benefits far beyond originally thought via a phenomenon known as neocollagenesis. 

HA is an endogenous polysaccharide found largely in skin and connective tissue. Loss of this substance is associated with aging and leads to increased volume depletion with subsequentdehydration and wrinkling. HA dermal fillers have been FDA approved and used in the United States for a decade as soft-tissue augmentation agents to enhance static contour defects related to aging, sun damage, acne or other traumatic incidences. Specifically, HA fillers were designed to provide temporary correction to the aforementioned defects by taking up physical volume. However, studies by Wang et al and Turlier et al have demonstrated 

neocollagenesis in patients who were injected with cross-linked HA fillers.1,2 These studies both showed increases in procollagen and matrix metalloproteinase (MMP) inhibitor expression around the 

We have qualitatively observed the neocollagenesis phenomenon in a patient who had a 1 time treatment with Restylane (Medicis Aesthetics Inc., Scottsdale, AZ) and continues to show impressive cosmetic results. This 50-year-old female had four 0.7-cc syringes of Restylane injected into her nasolabial folds and oral commissures in July 2005. She has returned in subsequent years for upper face botulinum toxin treatments, during which we took photos to evaluate her nasolabial/oral commissure region. Figures 1A and 1B show her prior to and immediately following her Restylane injections and Figure 1C shows her at a 4-day follow-up appointment after the Restylane injection. sites of filler injection as compared to placebo controls. Thus, it is now theorized that these HA fillers may have more permanent and longer lasting effects through both physical volume and de novo formation of collagen in the areas to which they are injected.


fig 1a


fig 1c

Figures 1A-C. Our patient in 2005 prior to hyaluronic acid (HA) injection, immediately post-HA injection and 4 days post-HA injection, respectively. Photos courtesy of Joel L. Cohen, MD (Colorado).

Figures 2 and 3 show subsequent visits in 2008 and 2013, respectively. This patient has displayed excellent improvement over baseline for as long as 8 years.

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 Figure 2. Our patient 3 years after hyaluronic acid injection (2008). Photos courtesy of Joel L. Cohen, MD (Colorado).

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 Figure 3. Our patient 8 years after hyaluronic acid injection (2013). Photos courtesy of Joel L. Cohen, MD (Colorado).

In the 2007 study of in vivo collagen stimulation, Wang et al explored the mechanisms behind potential neocollagenesis from injection of cross-linked HA fillers.1 They were able to prove that fibroblasts take on a more morphologically stretched shape and a more active phenotype as a result of HA fillers. HA injection, however, was not shown to have a direct stimulatory effect on fibroblasts. Instead, it was demonstrated and theorized that existing collagen fibers are stretched by HA injection, which imposes mechanical tension on surrounding fibroblasts. Therefore,  stimulating them to increase production of types I and III collagen. 

HA was also noticed to be more localized to areas of photodamaged or aged skin — where collagen is more fragmented. It is theorized that this localization of injected HA will preferentially allow for neocollagenesis in areas that need it the greatest. In addition, chemical cross-linking of the injected HA causes increased stability allowing for improved water binding and skin hydration.

Turlier et al further explored the phenomenon of de novo collagen expression via mechanical stimulation using high-frequency ultrasound and radiofrequency to measure injection volumes.2 Procollagen, MMP and MMP tissue inhibitors (TIMP-1) were also measured by ELISA and qPCR. They also found a statistically significant increase in procollagen, TIMP-1 and gene expression of procollagen I and III one month after injection. Procollagen levels remained elevated at 3 and 6 months of subsequent injections.

Neocollagenesis through the effects of HA fillers has been quantified in several studies. In this article, we present photo evidence of a patient who has seen lasting and excellent cosmetic results from HA injections far beyond that predicted from the product itself. Therefore, it stands to reason that de novo collagen formation in the nasolabial/oral commissure areas has facilitated these results, thus allowing for even better than anticipated outcomes in this patient who continues to be satisfied with her 1 time HA filler treatment.


Dr. Koger is a third year Dermatology resident at Northeast Regional Medical Center in Kirksville, Missouri and will be practicing in Boulder Colorado after graduation this year. She rotated with Dr. Cohen in November 2013.

Dr. Cohen is the director of AboutSkin Dermatology and DermSurgery in Colorado. His practice focuses on Mohs surgery and cosmetic dermatology.


Disclosure: Dr. Koger reports no relavent finacial relationships. 

Related to fillers, Dr. Cohen has worked with Medicis, Merz and Allergan. 



1. 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.

2. Turlier V, Dellalleau A, Casas C, et al. Association between collagen production and mechanical stretching in dermal extracellular matrix: in vivo effect of cross-linked hyaluronic acid filler. A randomized, placebo-controlled study. J. Dermatol Sci. 2013;69(3):187-194.

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