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Page 2 of 13 Yesantharao et al. Plast Aesthet Res 2022;9:60 https://dx.doi.org/10.20517/2347-9264.2022.67

Conclusion: Nanofibrillar collagen scaffolds have been demonstrated to effectively treat and/or prevent secondary
lymphedema in both preclinical and clinical investigations. Ultimately, these scaffolds represent a promising
intersection of tissue engineering and lymphedema therapy, and further clinical investigation is warranted.

Keywords: Biomaterials, lymphedema, biosynthetic scaffold, lymphangiogenesis, regenerative medicine, adipose-
derived stem cells

INTRODUCTION
Secondary lymphedema is a relatively common and highly morbid iatrogenic complication after cancer
[1]
resection, especially in those who undergo concomitant radiation therapy . In fact, amongst breast cancer
patients, some studies report secondary lymphedema incidence rates of greater than 50% . Thus, this
[2]
disease poses a substantial clinical and psychosocial burden amongst cancer survivors. Although diagnosis
and treatment of lymphedema have improved over the years, sustainable, replicable therapy has remained a
challenge.

Several techniques for the treatment of lymphedema have been developed, primarily aimed at redirecting
interstitial fluid back into lymphaticovenous channels to restore lymphatic flow. These treatments range
from conservative measures involving mechanical compression (i.e., complete decongestive therapy) to
microsurgical techniques designed to transpose lymphatic networks (i.e., vascularized lymph node transfer)
[3]
or to redirect lymphatic flow into the venous system (i.e., lymphovenous anastomosis) . More recently,
biomaterials-based treatments have emerged with a focus on augmenting/accelerating lymphatic
regeneration. Such treatments include nanofibrillar collagen scaffolds, which mimic the collagen
extracellular matrix in vasculature and can be seeded with stem cells or growth factors to help stimulate
[4]
lymphangiogenesis .
As survival improves amongst cancer patients, management of sequelae such as secondary lymphedema has
become paramount in ensuring long-term quality of life. There has been a recent surge in biomaterials
research for lymphedema treatment, with investigations spanning the gamut from preclinical studies
through clinical trials. This paper systematically reviews the current literature on biosynthetic nanofibrillar
collagen scaffolds for lymphedema treatment by reviewing recent innovations in the field and exploring
areas for further research.

METHODS
This was a systematic scoping review of the English-language literature investigating nanofibrillar collagen
scaffolds for the treatment of secondary lymphedema. A structured literature search was performed with the
MeSH terms listed in the Supplementary Tables 1-4, using databases including PubMed, MEDLINE,
EMBASE, Scopus, the Cochrane Central Register of Controlled Trials, and Web of Science. Covidence
management software (Melbourne, Australia) was utilized to screen, perform quality assessments, and
extract data from included literature. Studies were selected using predefined inclusion criteria created using
a Population, Intervention, Comparison, Outcome, Timing, and Setting (PICOTS) framework. Inclusion
criteria were as follows: (1) English-language; (2) original research article (i.e., not a review article or meta-
analysis) published after 1990; and (3) primarily investigating nanofibrillar collagen scaffolds for secondary
lymphedema treatment (including preclinical, translational, and clinical investigations). Reference sections
of articles meeting study criteria were also reviewed to identify any further relevant articles for study
inclusion.