In damaged skin, regeneration is not the same as filling and resurfacing. Healing by scarring results from the faulty, exuberant reconstruction of the dermal architecture and the formation of an epidermis lacking appendages. The overriding hypothesis of this multi-investigator proposal is that the MRL/MpJ mouse, in which ear wounds regenerate, expresses proteins during wound healing that favor regeneration. This concept is bolstered by our recently published work and our current findings that the MRL wound proteome has distinct differences from other mouse strains. We have published evidence that the bone marrow is a rich source of wound fibroblasts, and mesenchymal stem cells (MSC) from the MRL mouse enhance healing due in part to elevated sFRP-1. The first goal is to identify the key proteomic differences between regenerating and non-regenerating wounds within the MRL and between strains, using a novel, precise surgical method with the free-electron laser. Analysis will be accomplished with state of the art, high-resolution proteomic techniques and verified by immunohistochemistry. The second goal is to determine how the migration and differentiation of several stem cell populations is affected by known and newly-identified, regeneration-specific factors in a novel, microfluidic device that can generate complex, two-dimensional concentration gradients. Further validation will use novel wound chambers. The third goal is to build a scaffold, based on a novel polyurethane chemistry, to provide a three-dimensional environment into which factors that recruit stem cells or promote stem cell activity can be released, under controlled conditions, to drive a regenerative response in skin that normally heals by scarring. The project will test known candidates and then those newly identified. The key criteria for regeneration will be restoration of connective tissue architecture, including the formation of functional elastic fibers and the initiation of hair follicle formation. The translational outcome of this joint venture will be the identification of regeneration-promoting molecules, the use of bone marrow-derived cells to promote regeneration, the development of a new device for studying cell behavior, and the production of a bioactive scaffold for recruitment, differentiation, and delivery of morphogens that promote fully functional repair. This will be accomplished by the collaboration of a seasoned team of investigators with expertise in tissue analysis, proteomics, stem cell biology, microfluidics, and polymer chemistry.

Public Health Relevance

Wounds and burns frequently scar and fail to regenerate the original architecture of the skin. Certain strains of mice heal skin much better in some regions of their body, and part of this may be due to differences in their circulating stem cells or the way they are recruited to the wound. This is a study to identify the cell signals that differ between normal healing and regeneration, to see how they affect the behavior of stem cells, and to devise a temporary, synthetic scaffold that can deliver these regenerative signals to restore skin structure and function.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Musculoskeletal Tissue Engineering Study Section (MTE)
Program Officer
Tseng, Hung H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
Schools of Medicine
United States
Zip Code
Martin, John R; Nelson, Christopher E; Gupta, Mukesh K et al. (2016) Local Delivery of PHD2 siRNA from ROS-Degradable Scaffolds to Promote Diabetic Wound Healing. Adv Healthc Mater 5:2751-2757
Sidorov, Veniamin Y; Samson, Philip C; Sidorova, Tatiana N et al. (2016) I-Wire Heart-on-a-Chip I: Three-dimensional cardiac tissue constructs for physiology and pharmacology. Acta Biomater :
Taverna, Domenico; Pollins, Alonda C; Nanney, Lillian B et al. (2016) Histology-guided protein digestion/extraction from formalin-fixed and paraffin-embedded pressure ulcer biopsies. Exp Dermatol 25:143-6
Adolph, Elizabeth J; Guo, Ruijing; Pollins, Alonda C et al. (2016) Injected biodegradable polyurethane scaffolds support tissue infiltration and delay wound contraction in a porcine excisional model. J Biomed Mater Res B Appl Biomater 104:1679-1690
Park, Arick C; Phillips, Charlotte L; Pfeiffer, Ferris M et al. (2015) Homozygosity and Heterozygosity for Null Col5a2 Alleles Produce Embryonic Lethality and a Novel Classic Ehlers-Danlos Syndrome-Related Phenotype. Am J Pathol 185:2000-11
Taverna, Domenico; Pollins, Alonda C; Sindona, Giovanni et al. (2015) Imaging mass spectrometry for assessing cutaneous wound healing: analysis of pressure ulcers. J Proteome Res 14:986-96
Guo, R; Merkel, A R; Sterling, J A et al. (2015) Substrate modulus of 3D-printed scaffolds regulates the regenerative response in subcutaneous implants through the macrophage phenotype and Wnt signaling. Biomaterials 73:85-95
Guo, Ruijing; Ward, Catherine L; Davidson, Jeffrey M et al. (2015) A transient cell-shielding method for viable MSC delivery within hydrophobic scaffolds polymerized in situ. Biomaterials 54:21-33
Prieto, Edna M; Page, Jonathan M; Harmata, Andrew J et al. (2014) Injectable foams for regenerative medicine. Wiley Interdiscip Rev Nanomed Nanobiotechnol 6:136-54
Baquerizo Nole, Katherine L; Yim, Elizabeth; Van Driessche, Freya et al. (2014) Wound research funding from alternative sources of federal funds in 2012. Wound Repair Regen 22:295-300

Showing the most recent 10 out of 26 publications