Comparative Effects of Injectable Biostimulatory Agents (Calcium Hydroxyapatite, NCTF, VAMP and Human Exosomes) and Their Combination on Skin Regeneration

Abstract Background Injectable biostimulatory and bioactive agents are increasingly used to enhance dermal regeneration and improve skin quality. Polydeoxyribonucleotide (PDRN), polyrevitalizing multicomponent solutions, calcium hydroxylapatite microspheres, and human derived exosomes have been proposed to stimulate fibroblast activity, collagen remodeling, and angiogenesis. However, direct comparative evidence in intact skin remains limited. Objectives To compare the histological and angiogenic effects of PDRN, polyrevitalizing solutions, calcium hydroxylapatite, human derived exosomes, and their combination on dermal regeneration in intact skin using a hamster model. Methods One hundred sixty eight adult Syrian hamsters were randomized into seven groups (n = 24/group): untreated control, saline control, polyrevitalizing solution, PDRN, exosomes, calcium hydroxylapatite, and combination therapy. All treatments were administered subcutaneously (0.1 mL per site). Skin samples were collected at days 3, 7, and 14 (n = 8/group/timepoint). Histological evaluation included hematoxylin–eosin, Masson’s trichrome, and Van Gieson staining to assess dermal architecture and collagen organization. Angiogenesis was quantified using CD34 immunohistochemistry and microvessel density analysis. Results All active treatments increased dermal cellularity, collagen deposition, and microvessel density compared with control and saline groups. Combination therapy produced the greatest enhancements in collagen fiber density, organization, and angiogenesis, with significantly higher CD34 positive microvessel density at days 7 and 14 (p < 0.05 versus all single-agent groups). Among single agents, the polyrevitalizing solution (NCTF) demonstrated the most pronounced overall regenerative response, followed by VAMP (PDRN), Radiesse, and ASCE. Conclusions Injectable bioactive and biostimulatory agents enhance dermal remodeling and neovascularization in intact skin, with combination therapy targeting complementary regenerative pathways yielding the most pronounced histological effects. These findings support multimodal injectable strategies for skin rejuvenation and regenerative dermatology.