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Page 10 of 13 Yesantharao et al. Plast Aesthet Res 2022;9:60 https://dx.doi.org/10.20517/2347-9264.2022.67

Ultimately, nanofibrillar collagen scaffolds have been demonstrated to stimulate lymphangiogenesis when
used alone, in combination with cell-based therapy, and in combination with lymph node fragment transfer
or physiologic procedures such as lymphaticovenous anastomosis and vascularized lymph node transfer.
Furthermore, the use of BioBridge offers patients an adjunct procedure that can enhance results beyond a
physiologic procedure alone, even in late-stage secondary lymphedema, without incurring additional donor
[25]
site morbidity as would an additional lymph node transfer . Overall, while the specific indications for
BioBridge are still under investigation, this technology has demonstrated efficacy across several
lymphedema populations (i.e., primary therapy versus secondary therapy after previous physiologic
procedure) by helping to improve lymphedema symptoms and engendering targeted, functional
lymphangiogenesis. However, it should be noted that BioBridge therapy is thought to confer the greatest
efficacy in patients with excess fluid volume, as it aims to divert fluid back into lymphatic circulation. Thus,
for patients with severe, late-stage lymphedema and excess fibrofatty tissue, the use of this technology as a
primary or standalone therapy may be limited, and they may prefer to benefit from surgical debulking. With
regards to contraindications, those with allergic or anaphylactic reactions to the materials in the BioBridge
scaffold should not undergo scaffold implantation, and most included studies suggest that this scaffold
should not be implanted in infected fields . Those with evidence of cellulitis/soft tissue infection in the
[36]
affected extremity should first be treated with antibiotics prior to undergoing lymphedema surgery.

It is important to note that BioBridge represents a physiologic intervention that can be undertaken even in
clinical settings without microsurgical/supermicrosurgical capacity. This is especially encouraging for the
treatment of secondary lymphedema in low-resource settings when considering the data from
Hadamitzky et al., demonstrating significant improvement in limb volume with BioBridge placement and
[40]
autologous lymph node fragment transfer . While vascularized lymph node transfer is a more advanced
surgical technique, autologous lymph node fragment transfer with BioBridge placement is a relatively
simple procedure that can be performed without a microscope or complex surgical dissection. Thus, tissue
engineering approaches to secondary lymphedema treatment hold substantial promise in expanding
surgical treatment of lymphedema to a wider population of patients in need.

Future directions
Nanofibrillar collagen biosynthetic scaffolds have evolved out of a need to improve outcomes in patients
with acquired lymphedema. While current investigations have been largely observational, multi-center,
prospective randomized controlled trials are necessary to truly evaluate the efficacy of these scaffolds as a
viable treatment for secondary lymphedema. Currently, the clinical trial is underway comparing
vascularized lymph node transfer with BioBridge placement to vascularized lymph node transfer alone.
Further clinical trials should also investigate the preventive capacity of these scaffolds. There are many
efforts underway (e.g., LYMPHA) investigating the utility of microsurgical lymphedema treatments
[45]
undertaken in a preventative context . Future work should investigate the efficacy of pre-emptive scaffold
placement in patients undergoing lymph node dissection to forestall the development of lymphedema,
especially given promising preclinical results with preventative scaffold placement in rodent models of
lymphedema.

Additionally, further studies from a tissue engineering perspective are needed to optimize nanofibrillar
collagen scaffolds and maximize their potential for lymphangiogenesis (e.g., supplementing the scaffolds
with biochemical stimuli such as vascularized endothelial growth factor, or seeding the scaffolds with stem
cells). While most current efforts focus on recreating lymphatic vasculature, future work should also
investigate the feasibility of engineering constructs to regenerate the lymph node itself to obviate the need
for lymph node transfers .
[15]