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Rajaram et al. Plast Aesthet Res. 2025;12:6 https://dx.doi.org/10.20517/2347-9264.2024.147 Page 11 of 13

improvements in lymphangiogenesis compared to a control group.

Comparatively, no such adjuvant (outside of lymph node fragmentation) was used in any of the human
studies. PRP is readily available for human use in wound healing and aesthetic applications and may be used
in a clinical trial in lymphoedema patients. However, the consideration of tumorigenesis when using PRP
and VEGF-C in patients with a history of cancer must be balanced against potential benefits to
lymphangiogenesis. This may help explain the relative lack of adjuvant use in human studies.

Nevertheless, the induction of sterile inflammation in donor lymph nodes is specifically explored in animal
[14]
models by Joseph et al. for future use in human cancer populations . Their work purports that the
induction of sterile inflammation does not increase the risk of cancer recurrence in the same way that the
addition of pro-lymphangiogenic factors may.

Thus, the careful exploration of the carcinogenic capacity of PRP and VEGF-C, as well as the safety and
feasibility of inducing sterile inflammation in human studies, could help champion the use of adjuvants to
increase rates of lymphatic neogenesis.

Study design and characteristics
Finally, it must be noted that all available human evidence is relatively low in power and, therefore, cannot
be broadly extrapolated to all lymphoedema populations. The specificity of Belcaro et al.’s study, which
focuses on patients with lower limb, non-cancer lymphoedema, and the lack of a control group in both
Travis et al.’s cohort study and Brian et al.’s case report suggest that more research in humans is necessary
before a conclusive opinion about NVLNT in humans can be formed [20-22] . Furthermore, all included human
studies did not mention any adjuvant oncological therapy that patients underwent prior to the development
of lymphoedema such as radiation therapy. Currently, additional human clinical trials examining NVLNT
in a variety of lymphoedema populations are being undertaken and may shed more light on this technique
in the near future.

CONCLUSION
Lymphoedema is a painful and debilitating condition that affects hundreds of millions across the world.
Established management modalities for lymphoedema suffer from lack of efficacy, patient dissatisfaction,
and operative burden. Currently, a proof of concept for the minimally invasive procedure of NVLNT has
been shown in multiple animal models, with many demonstrating techniques to optimise
lymphangiogenesis in these models. However, research in humans is significantly less substantial. While
NVLNT appears generally safe in humans, it results in variable and possibly only modest improvements in
lymphoedema. The future of NVLNT may incorporate adjuvants, proven effective in animals, to bolster the
efficacy of NVLNT in humans such that an accessible and relatively burden-free solution to lymphoedema
can be found.

DECLARATIONS
Authors’ contributions
Investigation, resources, writing - original draft and editing: Rajaram R
Conceptualisation, resources, writing - original draft and editing: Cevik J
Conceptualisation, writing - editing, supervision: Rozen WM