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transfer OR lymphatic tissue transfer). During the review process, any relevant studies discovered through
references were also manually added. These papers underwent title and abstract screening, and selected
papers underwent full-text screening for final inclusion into the narrative review. These steps were
undertaken independently by two authors (RR and JC). The only stringent inclusion criterion for this
review is that the paper must explore NVLNT; all papers that mentioned the necessity for vascularisation of
tissue transfer were excluded. All human and animal experimental studies that covered a broad range of
clinical and experimental endpoints were included. Studies were analysed using a narrative synthesis and
discussed in the main text of this narrative review.

The current literature on NVLNT
Literature search and study characteristics
Out of 381 identified results, 144 duplicates were removed and 232 underwent title and abstract screening.
Of these, 210 were removed and 26 underwent full-text screening. During the full-text screening, 1 paper
was discovered through reference searching and was included manually. Ultimately, 17 papers were
included in this review.

Fourteen papers were controlled experimental animal studies examining a variety of animal species,
including mice, minipigs, sheep, and rabbits. These generally used experimental endpoints such as biopsy
and SPECT-CT to determine the efficacy of their various NVLNT techniques. Of the three human studies,
one was a controlled prospective trial, one was a single-arm retrospective cohort study, and one was a case
report. Volumetric analysis, functional scores, and patient-reported outcome measures were used to gauge
efficacy [Table 1].

Mechanisms for NVLNT
The regeneration of grafted lymphatic tissue has been documented since the 1920s when studies by Jaffe and
Richter demonstrated in animal models that portions of the thymus could be avascularly grafted and
[7]
demonstrate regrowth at a distant site . However, controversy has surrounded the idea that a similar
grafting process was possible with lymph nodes. While opposition to this notion through the work of Tilak
[8]
and Howard in 1965 believed that vascular supply needed to be preserved to support lymphangiogenesis ,
the work of Pabst and Rothkötter in 1988 demonstrated that grafted lymph nodes could induce
lymphangiogenesis without the presence of a donor blood supply .
[9]
Mechanisms for lymphangiogenesis in a grafted lymph node have not been thoroughly elucidated.
[10]
However, existing literature on direct lymphangiogenesis (without grafting) proposed pathways to
lymphangiogenesis in vascularised models, and the amalgamation of experimental studies can be used to
theorise a process of imbibition, cell-mediated lymphangiogenesis and maturation and remodelling. To this
end, lymphangiogenesis of a grafted lymph node is similar to that of skin graft take .
[10]

Imbibition
In the first hours to days after lymph nodes have been transplanted into a new site, they survive based on
the diffusion of oxygen and nutrients into cells. However, this is only a temporary measure and does not
provide a sufficiently nutritive environment for lymph nodes to continue to survive [Figure 1] .
[11]
Cell-mediated lymphangiogenesis
In response to an unfavourable cellular environment, pro-lymphangiogenic factors such as VEGF-C,
VEGF-A, and fibroblast growth factor are released by B cells, endothelial cells, and platelets to the grafted
lymph node . These factors bind to receptors on lymphatic endothelial cells, such as VEGF-A/C binding to
[12]