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Page 6 of 13 Yesantharao et al. Plast Aesthet Res 2022;9:60 https://dx.doi.org/10.20517/2347-9264.2022.67

Table 1. Summary of preclinical investigations
Number
Study Objectives Study Treatments of Timeline/Duration Study outcomes
(reference)* design animals
Small animal
Nguyen et al., To investigate the Randomized (1) Untreated n = 7 BioBridge was implanted BioBridge implantation
2022 [32] efficacy of BioBridge Factorial controls prevention immediately in the at the time of lymph
implantation both Design (2 (2) BioBridge after group; preventive group, and 1 node excision prevented
preventatively and as treatment lymphadenectomy n = 5 month after the lymphedema
a treatment in a groups) but prior to treatment establishment of development. BioBridge
rodent model of radiation group lymphedema in the seeded with stem cells
acquired (preventive) treatment group, study also had therapeutic
lymphedema. (3) BioBridge + data were collected up to effects in rodents with
Outcomes were autologous 4 months after scaffold established
measured using CT- adipose-derived implantation lymphedema, with
based volumetric stem cells demonstrated
analysis and near- (treatment) regeneration of
infrared fluoroscopy lymphatic vasculature
to detect lymphatic
regeneration
Large animal
Hadamitzky et al., To investigate the Randomized (1) Untreated n = 4 BioBridge was implanted 3 BioBridge treatment
[33]
2016 efficacy of BioBridge Factorial controls control; months after with or without lymph
scaffold placement Design (2 (2) BioBridge + n = 4 establishment of node transfer
+/- concurrent treatment VEGF-C BioBridge + lymphedema; study data significantly improved
vascularized lymph groups) (3) BioBridge + VEGF-C; were collected up to 3 bioimpedance ratios
node transfer in a lymph node n = 8 months after scaffold and increased
porcine model of fragments BioBridge + implantation quantifiable lymphatic
acquired lymph collectors in the treated
lymphedema. node area, indicating targeted
Outcomes were fragments regeneration of
assessed using functional lymphatic
bioimpedance, vessels. VEGF-C, on the
histologic evaluation, other hand, was found
and computed to hinder directional
tomography imaging lymphangiogenic
of lymphatic vessels sprouting
in the treated limb

*See References section for full citation; citation number on References list provided here in parentheses. VEGF-C: Vascular endothelial growth
factor-C; VLNT: vascularized lymph node transfer.

lymphangiography. This study demonstrated that BioBridge implantation significantly enhanced lymphatic
regeneration when placed alone or in combination with autologous lymph node fragment transfer. Animals
treated with BioBridge demonstrated a significantly greater density of lymphatic vessels. In fact, the highest
density of lymphatic vessels in treated animals was found within 100 microns of the scaffold, demonstrating
the specific impact that the scaffold had on augmenting lymphatic regeneration. Upon computed
tomography imaging and bioimpedance testing, the BioBridge treatment group with concurrent autologous
lymph node fragment transfer demonstrated functional improvement in lymphedema symptoms compared
to the control group. In experimental groups treated with VEGF-C impregnated scaffolds, however, it was
found that exogenous VEGF-C resulted in nonfunctional lymphangiogenesis. The presence of growth factor
distributed uniformly along the length of the scaffold obscured the directionality of lymphatic regeneration,
resulting in ineffectual lymphangiogenesis.

Nanofibrillar collagen scaffolds: clinical investigations
Nanofibrillar collagen scaffolds have also been investigated in humans, with preliminary results
demonstrating the safety of scaffold placement as well as success in improving lymphedema symptoms
[Table 2]. Study eligibility criteria are reported in Table 2 - including studies that investigated BioBridge
placement in lymphedema patients across a variety of stages (stage I-III), as both a primary treatment and a
secondary procedure in patients who had already undergone prior physiologic therapy (e.g., LVA, VLNT).