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Yesantharao et al. Plast Aesthet Res 2022;9:60 https://dx.doi.org/10.20517/2347-9264.2022.67 Page 3 of 13

[5]
The study workflow was designed according to PRISMA guidelines . Two independent study team
members screened article titles, abstracts, and full texts for every article identified through a comprehensive
literature search. Only articles primarily investigating nanofibrillar collagen scaffolds for lymphedema
treatment were selected for final inclusion in the review. Any discrepancies in screening results were
resolved through reviewer consensus. Two independent team members assessed the risk of bias for each
article included in the final study cohort using the validated Risk of Bias in Non-Randomized Studies of
Interventions (ROBINS-I) scale for clinical work and the SYRCLE’s risk of bias tool for animal studies .
[6,7]
Study objectives, design, interventions, results, and conclusions were extracted for each included study.
Study data were tabulated to synthesize the literature on the use of biosynthetic nanofibrillar collagen
scaffolds for lymphedema treatment.

RESULTS
In total, 32 English language articles were identified from the initial query, of which eight articles specifically
investigating nanofibrillar collagen scaffolds for secondary lymphedema were selected for inclusion in the
final review. Figure 1 demonstrates the algorithm for the selection of the final set of articles included in this
study.

All included articles were either preclinical investigations of biosynthetic nanofibrillar collagen scaffolds for
lymphedema treatment in animal models of lymphedema, or clinical cohort studies of these scaffolds in
human subjects. The overall risk of bias was moderate for two studies and low for six studies
[Supplementary Figure 1]. Additionally, all articles provided details on surgical techniques used to implant
the scaffolds, whether in animal models or human subjects, as well as postoperative outcomes regarding
changes in lymphedema symptoms following implantation of the biosynthetic scaffolds.

DISCUSSION
Novel tissue engineering efforts in lymphedema treatment have focused on designing scaffolds to guide and
enhance lymphangiogenesis to regenerate lymphatic channels after iatrogenic injury. A number of
biomaterials have been studied in the context of promoting lymphatic regeneration, ranging from
endothelial cell-seeded polyglycolic acid scaffolds, fibrin/fibrin-collagen matrices, and fibrin hydrogels to
bioengineered dermal grafts/acellular dermal matrices and decellularized adipose tissue matrices [8-11] . In
particular, nanofibrillar collagen scaffolds have demonstrated particular efficacy in enhancing
lymphangiogenesis . From a review of both preclinical and clinical investigations, these nanofibrillar
[4]
biosynthetic collagen scaffolds have been demonstrated to improve outcomes in secondary lymphedema
across both preventative and therapeutic contexts [Figure 2].

Biosynthetic scaffolds: background
Lymphatic vessels have a unique architecture that is challenging to recapitulate . A current focus of tissue
[12]
engineering for lymphedema treatment involves the fabrication of biosynthetic scaffolds, which can be
implanted in affected extremities to encourage lymphangiogenesis. These scaffolds are designed to function
as three-dimensional templates for endothelial cell proliferation by acting as analogues to the extracellular
matrix found in the native lymphatic vasculature. The biodegradable scaffolds are designed to be replaced
by functional lymphatic channels over time. Furthermore, they can be used in combination with pro-
lymphangiogenic growth factors or cell-based therapy by seeding the scaffold with growth factors or stem
cells known to be involved in lymphangiogenesis [13,14] .

Multiple biomaterials have been investigated as scaffolds for lymphangiogenesis, including polyglycolic
acid/polylactic acid, human acellular dermal matrix, decellularized adipose tissue matrix, fibrin matrices in