# Use of skin grafts programmed to express VEGF-C with biosensor feedback regulation to treat lymphedema

> **NIH NIH R21** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $199,014

## Abstract

PROJECT SUMMARY
 Lymphedema is a morbid musculoskeletal and skin condition affecting a broad population of patients. In the
United States, this condition primarily affects individuals who have had lymph node surgery for cancer
management; worldwide over 300 million individuals are affected due to lymphatic infection. The affected limb
becomes swollen, and develops skin thickening and fibroadipose tissue deposition. Patients experience pain,
impaired limb function, chronic wounds, and are at risk for secondary tumors (lymphangiosarcoma).
 Unfortunately, current therapeutic strategies to treat lymphedema have had limited success. Non-operative
management including compression wraps, manual lymphatic drainage, and pneumatic pumps require strict
adherence and are time-consuming for patients. Surgical approaches have demonstrated efficacy but require
specialized surgical equipment and technical training, limiting the ability to provide this option to the 5+ million
affected individuals in the United States. Vascular endothelial growth factor-C (VEGF-C) is a known pro-
lymphangiogenic growth factor which has been studied as a drug-based approach to treat secondary
lymphedema. Delivery strategies such as adenoviral vectors, scaffolds, and repeat injection have provided
important proof-of-concept support for VEGF-C. However, clinical translation has not been realized.
 Over the past several years, our laboratory has developed a novel technology enabling epidermal stem cells
to undergo gene-editing to express biologics of interest. These stem cells are cultured in vitro to produce skin
grafts which can be applied to the patient. Our approach has demonstrated efficacy treating diabetes and
cocaine abuse through systemic bioavailability in mouse models. In this proposal, we will build on our previous
findings to bring this technology closer to clinical utility while broadening its application.
 First, we will program epidermal stem cells to express VEGF-C and culture these stem cells in vitro, to form
skin grafts. To bring us closer to clinical translation, epidermal stem cells will be isolated from human skin. We
will demonstrate that skin grafts can produce growth factors for local bioavailability, thereby expanding the use
of this technology. We will use these skin grafts in a model of hindlimb lymphedema, thereby demonstrating
that this technology has the potential for clinical utility to treat lymphedema isolated to a unilateral limb.
Second, we will advance the current skin graft technology by introducing a biosensor mechanism which
provides negative feedback regulation of VEGF-C expression. This biosensor will positively impact the
translational potential of this therapy, and have broader utility for translation of in vivo “bioreactor” grafts.
 Upon conclusion of this study, we will have addressed a challenging morbidity experienced by cancer patients
(secondary lymphedema), using a novel technology (programmed epidermal stem cells) to expand its uti...

## Key facts

- **NIH application ID:** 10042514
- **Project number:** 1R21AR077769-01
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Shailesh Agarwal
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $199,014
- **Award type:** 1
- **Project period:** 2020-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10042514

## Citation

> US National Institutes of Health, RePORTER application 10042514, Use of skin grafts programmed to express VEGF-C with biosensor feedback regulation to treat lymphedema (1R21AR077769-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10042514. Licensed CC0.

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