Department of Plastic and Reconstructive, Shanghai Ninth People’s Hospital affilicated to Medical School of Shanghai Jiao Tong University, Shanghai 200011, China.
Correspondence Address: Prof. Yu-Guang Zhang, Department of Plastic and Reconstructive, Shanghai Ninth People’s Hospital affilicated to Medical School of Shanghai Jiao Tong University, No. 639 Zhi Zao Ju Road, Shanghai 200011, China. E-mail: firstname.lastname@example.org
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License (http://creativecommons.org/licenses/by-nc-sa/3.0/), which allows others to remix, tweak and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
With the development of autologous stem cells transplantation, the application of autologous fibroblast graft has been an important therapy in defect repair. In the past decade, amounts of studies have reported favorable treatment effect and safety about the therapy. The material has the ability to produce human collagen in vivo. This article details recent scientific work of the cases, effect, injection technique, complications and safety of autologous fibroblast injection treatment.
Autologous fibroblast, injection, aging skin
Wrinkles can be corrected by using various treatment methods like lasers, soft tissue fillers, Botox for dynamic wrinkles, and so on. The most common therapy is dermal fillers like hyaluronic acid. However, dermal fillers are typically degradable or semipermanent, and liable to allergic reaction or other side reactions like skin necrosis, visual impairment. Autologous materials have been used for more than a century for soft tissue augmentation. Autologous fat has always been the first choice of autologous graft. However, the high rate of graft resorption and unpredictable degree of volume loss in some degree reduced the enthusiasm for the use of adipose grafts in soft tissue augmentation. With the development of autologous stem cells transplantation, the application of autologous fibroblast graft has been an important therapy in defect repair.[3-7] Fibroblasts are the main functional cells in dermis and autologous fibroblasts injection may be more beneficial than other therapies in facial rejuvenation. Autologous fibroblasts injection is not a common kind of dermal filler, that is to say, it is not volume filler. As a result, it’s very important to notify patients that the therapy does not take effect in a short time. Fibroblasts show mitigating improvement after about 3 serial treatment processes and living cells keep vigorous growth that may lead to greater persistence than other fillers. Autologous cultured fibroblasts have been used effectively for dermal and subcutaneous deficiencies since 1995. Autologous fibroblast transplantation first received approval from the US Food and Drug Administration in June 2011 to improve moderate or severe nasolabial fold wrinkles.
In the past decade, amounts of studies have reported favorable treatment effect and safety about the therapy.[11-13] Clinical researches for autologous fibroblast therapy have been carried on since 2001. Cultured autologous fibroblasts have been utilized effectively to treat various wrinkles, depressed scars, acne irregularities, wounds and atrophy.[16,17]
In 2007, Weiss et al. in America reported a double-blind, randomized comparison on autologous fibroblast injection and placebo for facial contour defects treatment. Results showed that autologous fibroblasts generated statistically significantly greater improvements in dermal deformities and acne scars than did placebo. The difference between fibroblast injections and placebo obtained statistical significance at 6 months (P < 0.0001). Patients treated with autologous fibroblasts continuously show benefit at 9-month and 12-month follow-up. There were no serious treatment-related adverse events in this study.
In 2012, Smith et al. reported a multicenter, double-blind, placebo-controlled trial of autologous fibroblast therapy to treat nasolabial fold wrinkles. A large sample including 372 subjects was enrolled in this trial. There were comparisons between subjects treated with cultured autologous fibroblast and placebo. The results showed at least 1-point improvement on both subject and evaluator assessment after 6 months (P < 0.001).
In 2012, in a South American study, Eça et al. published the results of their search about the safety and efficacy of dermal regeneration with the injection of young autologous fibroblasts obtained from patients themselves. With 4 injections given at 15-day intervals after 60 days, periorbital tonicity had improved obviously. Nevertheless, there was little improvement in surface lines and no improvement at all in deeper wrinkles.
In 2013, Munavalli et al. in America reported a randomized multicenter, prospective, double-blind, placebo-controlled clinical trial about the treatment of bilateral moderate to severe acne scars using autologous fibroblasts. Ninety-nine subjects underwent three intradermal injection sessions at 14-day intervals. They were injected autologous fibroblast suspension on one cheek and cell culture medium on the other cheek. The outcome showed that autologous fibroblast had significantly greater efficacy than vehicle control (cell culture medium).
Different anesthesia forms are provided at the discretion of the investigator. A topical anesthetic cream containing 4% lidocaine may be applied. The areas of treatment are swabbed with an antiseptic before injections.
Autologous fibroblast suspension or placebo is injected using a 1-mL syringe and a 29- or 30-G needle. A retrograde linear threading technique is utilized. The suspension is placed into the superficial papillary dermis. Create a wheal and transient blanching of the skin surface with each injection. The current injection dose is 0.1 mL of suspension with a concentration of (1.0-2.0) × 107 cells/mL. During the injection, doctors should pay attention to the following points:
• No lidocaine or epinephrine is mixed to the cell suspension before injection to avoid the negative impact on the viability of the cells.
• No massage or other manipulation of the areas is performed to avoid damaging or altering the cells.
• No soaps, cosmetics, or any other products are used to the injection sites for 72 h after operation. Limited short-term indirect application of ice to the treatment area was allowed but not recommended.
Injections can be given in the forehead wrinkles, perioral wrinkles, nasolabial fold, chin, and periorbital wrinkles with a minimal interval of 15 days between each session. The injection technique has no obvious difference among these different injected sites.
There is no record in the scientific literature of any case of tumor formation resulting from the stem cell injection since the first transplants of adult stem cells from bone marrow in the 1960s and the transplant of adult stem cells from umbilical cord blood in 1988.
Autologous fibroblast therapy has been considered to be safe and well tolerated in amounts of researches. The wrinkle improvement during this treatment is different from most dermal fillers. The product results in the accumulation of new collagen but not direct volume replacement. Consequently, it has a more gradual onset of effect than which has been seen immediate correction from other dermal fillers.
Autologous fibroblast therapy has adverse events including: local redness, bruising, swelling, bleeding, pain or irritation, erythema, developing nodules, nausea, headache and so on. The most common adverse events reported were redness, swelling, and bruising in and around the treatment areas. The severity of majority of adverse events is mild to moderate and probably related to the process of injection.
Autologous fibroblast treatment is a novel therapeutic method for treating dermal defects. The material has the ability to produce human collagen in vivo. In sum, autologous fibroblasts injection has the following characteristics: (1) it’s not a volume filler; (2) injection level is more superficial; (3) need a period of time (about 6 months) to take effect; (4) treatment effect on fine lines like nasolabial wrinkles is better; (5) need additional costs and processes for harvesting and culturing fibroblasts before injection; and (6) adverse reactions are minimal and comparable with other common injection. Although the favorable outcomes have been obtained from various studies, the specific cellular and molecular biologic mechanism remains unknown. They may take effect through single or several signal pathways that could cause direct synthesis of increased amounts of collagen and elastin, proliferation of fibroblasts and the deposition of cofactors. This may be the long-term goal of the autologous fibroblast transplantation research.
There are no conflicts of interest.
1. Carruthers JD, Fagien S, Rohrich RJ, Weinkle S, Carruthers A. Blindness caused by cosmetic filler injection: a review of cause and therapy. Plast Reconstr Surg 2014;134:1197-201.DOIPubMed
2. Illouz YG. Present results of fat injection. Aesthetic Plast Surg 1988;12:175-81.DOIPubMed
3. You HJ, Han SK, Rhie JW. Randomised controlled clinical trial for autologous fibroblast-hyaluronic acid complex in treating diabetic foot ulcers. J Wound Care 2014;23:521-2, 524, 526-30.DOIPubMed
4. Milinkovic I, Aleksic Z, Jankovic S, Popovic O, Bajic M, Cakic S, Lekovic V. Clinical application of autologous fibroblast cell culture in gingival recession treatment. J Periodontal Res 2015;50:363-70.DOIPubMed
5. Morimoto N, Ito T, Takemoto S, Katakami M, Kanda N, Tada H, Tanaka S, Teramukai S, Kawai K, Nakamura Y, Kasai Y, Masayuki Y, Maekawa T, Shimizu A, Suzuki S. An exploratory clinical study on the safety and efficacy of an autologous fibroblast-seeded artificial skin cultured with animal product-free medium in patients with diabetic foot ulcers. Int Wound J 2014;11:183-9.DOIPubMed
6. Pichler R, Klima G, Richter E, Marksteiner R, Mayr V, Skradski V, Horninger W, Oswald J. Autologous fibroblast transplantation at the vesico-ureteral junction as potential reconstructive cell replacement in an animal model. World J Urol 2013;31:169-74.DOIPubMed
7. Malecki M. Improved targeting and enhanced retention of the human, autologous, fibroblast-derived, induced, pluripotent stem cells to the sarcomeres of the infarcted myocardium with the aid of the bioengineered, heterospecific, tetravalent antibodies. J Stem Cell Res Ther 2013;3:pii138.DOI
8. Martin I, Baldomero H, Bocelli-Tyndall C, Slaper-Cortenbach I, Passweg J, Tyndall A. The survey on cellular and engineered tissue therapies in Europe in 2009. Tissue Eng Part A 2011;17:2221-30.DOIPubMedPMC
9. Weiss RA. Autologous cell therapy: will it replace dermal fillers? Facial Plast Surg Clin North Am 2013;21:299-304.DOIPubMed
10. Boss WK Jr, Usal H, Fodor PB, Chernoff G. Autologous cultured fibroblasts: a protein repair system. Ann Plast Surg 2000;44:536-42.DOI
11. Shevtsov MA, Galibin OV, Yudintceva NM, Blinova MI, Pinaev GP, Ivanova AA, Savchenko ON, Suslov DN, Potokin IL, Pitkin E, Raykhtsaum G, Pitkin MR. Two-stage implantation of the skin- and bone-integrated pylon seeded with autologous fibroblasts induced into osteoblast differentiation for direct skeletal attachment of limb prostheses. J Biomed Mater Res A 2014;102:3033-48.DOIPubMedPMC
12. Munavalli GS, Smith S, Maslowski JM, Weiss RA. Successful treatment of depressed, distensible acne scars using autologous fibroblasts: a multi-site, prospective, double blind, placebo-controlled clinical trial. Dermatol Surg 2013;39:1226-36.DOIPubMedPMC
13. Jin Z, Wu YG, Yuan YM, Peng J, Gong YQ, Li GY, Song WD, Cui WS, He XY, Xin ZC. Tissue engineering penoplasty with biodegradable scaffold Maxpol-T cografted autologous fibroblasts for small penis syndrome. J Androl 2011;32:491-5.DOIPubMed
14. Munavalli GS, Smith S, Maslowski JM, Weiss RA. Successful treatment of depressed, distensible acne scars using autologous fibroblasts: a multi-site, prospective, double blind, placebo-controlled clinical trial. Dermatol Surg 2013;39:1226-36.DOIPubMedPMC
15. Morimoto N, Kakudo N, Valentin Notodihardjo P, Suzuki S, Kusumoto K. Comparison of neovascularization in dermal substitutes seeded with autologous fibroblasts or impregnated with bFGF applied to diabetic foot ulcers using laser Doppler imaging. J Artif Organs 2014;17:352-7.DOIPubMed
16. Zhao Y, Wang J, Yan X, Li D, Xu J. Preliminary survival studies on autologous cultured skin fibroblasts transplantation by injection. Cell Transplant 2008;17:775-83.DOIPubMed
17. Milinkovic I, Aleksic Z, Jankovic S, Popovic O, Bajic M, Cakic S, Lekovic V. Clinical application of autologous fibroblast cell culture in gingival recession treatment. J Periodontal Res 2015;50:363-70.DOIPubMed
18. Weiss RA, Weiss MA, Beasley KL, Munavalli G. Autologous cultured fibroblast injection for facial contour deformities: a prospective, placebo-controlled, phase III clinical trial. Dermatol Surg 2007;33:263-8.DOI
19. Smith SR, Munavalli G, Weiss R, Maslowski JM, Hennegan KP, Novak JM. A multicenter, double-blind, placebo-controlled trial of autologous fibroblast therapy for the treatment of nasolabial fold wrinkles. Dermatol Surg 2012;38:1234-43.DOIPubMed
20. Eça LP, Pinto DG, de Pinho AM, Mazzetti MP, Odo ME. Autologous fibroblast culture in the repair of aging skin. Dermatol Surg 2012;38:180-4.DOIPubMed
21. Thomas ED, Lochte HL Jr, Cannon JH, Sahler OD, Ferrebee JW. Supralethal whole body irradiation and isologous marrow transplantation in man. J Clin Invest 1959;38:1709-16.DOIPubMedPMC
22. Gluckman E, Broxmeyer HA, Auerbach AD, Friedman HS, Douglas GW, Devergie A, Esperou H, Thierry D, Socie G, Lehn P. Hematopoietic reconstitution in a patient with Fanconi's anemia by means of umbilical-cord blood from an HLA-identical sibling. N Engl J Med 1989;321:1174-8.DOIPubMed
23. Lamme EN, Van Leeuwen RT, Brandsma K, Van Marle J, Middelkoop E. Higher numbers of autologous fibroblasts in an artificial dermal substitute improve tissue regeneration and modulate scar tissue formation. J Pathol 2000;190:595-603.DOI
Gabriel Pignata et al., Plastic and Aesthetic Research, 2018
Ehsun Naeem et al., Hepatoma Research, 2018
Betul Gozel Ulusal et al., Plastic and Aesthetic Research, 2018
Srilekha Sridhara et al., Journal of Unexplored Medical Data, 2018
Angelo Andriulli et al., Journal of Unexplored Medical Data, 2017
Youssef Tahiri et al., Plastic and Aesthetic Research, 2015