Advances in the research of autologous fibroblast injections for aging skin

Introduction

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.^[1] 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.^[2] 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.^[8] 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.^[9] Autologous cultured fibroblasts have been used effectively for dermal and subcutaneous deficiencies since 1995.^[10] Autologous fibroblast transplantation first received approval from the US Food and Drug Administration in June 2011 to improve moderate or severe nasolabial fold wrinkles.

Cases and treatment outcome

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,^[14] wounds^[15] and atrophy.^[16,17]

In 2007, Weiss et al.^[18] 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.^[19] 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.^[20] 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.^[12] 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).

Injection technique

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.^[19]

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.

Complications and safety

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^[21] and the transplant of adult stem cells from umbilical cord blood in 1988.^[22]

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.^[19]

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.

Conclusion

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.^[23] This may be the long-term goal of the autologous fibroblast transplantation research.