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

compression garments and achieve endogenous volume control in the affected extremity through the
physiologic restoration of lymphatic circulation [36,38] .

While the previously described work demonstrated successful placement of BioBridge as a delayed therapy
after a physiologic procedure, a recent case report in a patient with stage III right lower extremity secondary
lymphedema has demonstrated that BioBridge implantation is also successful in normalizing limb volume
[39]
when implanted concurrently with vascularized lymph node transfer . Notably, this patient also had
radiation-related peripheral vascular disease and peripheral neuropathy in the affected limb, and had
undergone prior revascularization with a saphenous vein graft due to radiation-induced femoral artery
thrombosis. In this patient, BioBridge scaffolds were placed subcutaneously after scar release at the time of
vascularized lymph node transfer to provide soft tissue support and to bridge the lymph node transfer to
healthy native lymph tissue. Ultimately, vascularized lymph node transfer in combination with BioBridge
placement resulted in sustained limb volume reduction, improved neuropathic pain, and improved
ambulation three months post-procedurally, demonstrating that nanofibrillar collagen scaffolds can also be
safely placed at the time of microsurgical physiologic lymphedema procedures.

Preliminary data in secondary lymphedema patients have also demonstrated that BioBridge scaffolds seeded
with adipose-derived stromal cells in combination with non-vascularized autologous lymph node fragment
[40]
transfer resulted in sustained improvement in lymphedema symptoms . A majority of patients treated with
seeded BioBridge scaffolds and lymph node fragment transfer demonstrated substantial volume reduction
in the affected extremity at 6 months postoperatively (mean volume reduction reported was 20%, with 1/3
of the patients reporting complete normalization of limb volumes), compared to a 1% volume reduction in
controls who received lymph node fragment transfer alone. These results highlight the specific, synergistic
effect of BioBridge scaffolds in enhancing lymphangiogenesis, given that lymph node fragment transfer
alone was not enough to create measurable improvements in lymphedema symptoms.

Finally, Dionyssiou et al. (2021) investigated simultaneous breast and lymphedema reconstruction . In this
[41]
study, collagen scaffolds were subcutaneously inserted in the upper limb, in combination with pedicled or
free vascularized lymph node transfer, to enhance lymphangiogenesis during partial or total breast
reconstruction. Treated patients had fewer episodes of infection, significantly reduced pain and heaviness,
significantly improved overall function, and evidence of dermal backflow reduction at 1 year postoperative
follow-up. No complications specifically related to collagen scaffold placement were reported.

Nanofibrillar collagen scaffolds in the context of current lymphedema treatment
Regenerative medicine holds immense promise for secondary lymphedema and represents the cutting-edge
therapies in this field that have the potential for curative treatment [13,42,43] . Tissue engineering efforts with
nanofibrillar collagen scaffolds offer a number of advantages over current standard-of-care therapies for
secondary lymphedema as it provides a biomaterial structure that can mimic native extracellular matrix and
[44]
drive lymphatic regeneration in synergy with cellular and biochemical growth factors . Unlike
physiotherapy with drainage and compression or ablative surgical procedures, these scaffolds have the
potential to obviate the need for repeat surgery or lifelong therapy, and they directly address the
[15]
pathophysiology of the disease rather than simply providing symptomatic treatment . Compared to
physiologic procedures (e.g., vascularized lymph node transfer, lymphaticovenous anastomosis),
nanofibrillar collagen scaffolds are minimally invasive, placed subcutaneously in affected limbs to encourage
lymphatic flow across scar tissue, and do not require microsurgical anastomoses or a donor site.