Transplantation for organ failure is limited by the problems of organ scarcity and the need for lifelong immunosuppression. Tissue engineering holds the promise to create new organs outside the human body but has been hindered by 1.) the inability to adequately vascularize tissue constructs and 2.) the inability to efficiently re-integrate these tissues into the systemic circulation. Classical approaches to tissue engineering using cells seeded onto resorbable matrices have had success in replicating simple structures but have been unable to create complex parenchymal organs because of the difficulty in creating patterned vascular networks. To solve this problem, we have developed a novel approach to engineer constructs of organ-level complexity by using pre-existing, explanted microcirculatory beds as the scaffold for tissue engineering. Since this approach starts with the vascular network as a foundation, it builds autologous tissue from the """"""""inside-out,"""""""" in a manner similar to embryonic development or stem cell mediated tissue regeneration. During our previous NIH funding period, we demonstrated an ability to sustain explanted vascular beds for extended periods ex vivo (48-72hrs), genetically modify their growth milieu, and efficiently seed them with progenitor cells creating functional neo-organ units for re-implantation. Based on this success, we postulate that more prolonged cultivation of explanted microcirculatory beds will permit generation of autologous vascularized neo-organs which can reliably substitute a functional or physiologic role for a failing organ. In this proposal, Specific Aim 1 will define the perfusion conditions necessary for reliable viability, growth, and directed manipulation of explanted microcirculatory beds for 3-14 days ex vivo.
In Specific Aim 2, the optimal seeding and differentiation conditions of infused progenitor cells to generate vascularized neo-organs will be determined. Finally, Specific Aim 3 will investigate the durability and functional capacity of re-implanted vascularized neo-organ units to fulfill a physiologic role in vivo. We believe this """"""""inside-out"""""""" approach to tissue engineering will facilitate the generation of vascularized organ-level constructs by specifically addressing the critical issues that preclude success in other tissue engineering paradigms.

Public Health Relevance

Tissue engineering holds the promise to create new organs but progress has been limited by poor vascularization of tissue constructs and ineffective re-integration of these tissues into the systemic circulation. To address this problem, we have developed a novel approach to engineer organ-level constructs by using pre-existing, explanted microcirculatory beds as an autologous scaffold for tissue regeneration. Our initial results demonstrate that viable microcirculatory beds can be maintained ex vivo, seeded with progenitor cells, and transfected to produce therapeutic peptides - all critical initial steps toward generating vascularized organ- level constructs.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
Project #
Application #
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Hunziker, Rosemarie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
Rennert, Robert C; Januszyk, Michael; Sorkin, Michael et al. (2016) Microfluidic single-cell transcriptional analysis rationally identifies novel surface marker profiles to enhance cell-based therapies. Nat Commun 7:11945
Rodrigues, Melanie; Wong, Victor W; Rennert, Robert C et al. (2015) Progenitor cell dysfunctions underlie some diabetic complications. Am J Pathol 185:2607-18
Duscher, Dominik; Maan, Zeshaan N; Whittam, Alexander J et al. (2015) Fibroblast-Specific Deletion of Hypoxia Inducible Factor-1 Critically Impairs Murine Cutaneous Neovascularization and Wound Healing. Plast Reconstr Surg 136:1004-13
Tevlin, R; Atashroo, D; Duscher, D et al. (2015) Impact of surgical innovation on tissue repair in the surgical patient. Br J Surg 102:e41-55
Duscher, Dominik; Rennert, Robert C; Januszyk, Michael et al. (2014) Aging disrupts cell subpopulation dynamics and diminishes the function of mesenchymal stem cells. Sci Rep 4:7144
Rennert, Robert C; Sorkin, Michael; Januszyk, Michael et al. (2014) Diabetes impairs the angiogenic potential of adipose-derived stem cells by selectively depleting cellular subpopulations. Stem Cell Res Ther 5:79
McArdle, Adrian; Senarath-Yapa, Kshemendra; Walmsley, Graham G et al. (2014) The role of stem cells in aesthetic surgery: fact or fiction? Plast Reconstr Surg 134:193-200
Wong, Victor W; Sorkin, Michael; Gurtner, Geoffrey C (2013) Enabling stem cell therapies for tissue repair: current and future challenges. Biotechnol Adv 31:744-51
Rennert, Robert C; Rodrigues, Melanie; Wong, Victor W et al. (2013) Biological therapies for the treatment of cutaneous wounds: phase III and launched therapies. Expert Opin Biol Ther 13:1523-41
Rennert, Robert C; Sorkin, Michael; Garg, Ravi K et al. (2012) Stem cell recruitment after injury: lessons for regenerative medicine. Regen Med 7:833-50

Showing the most recent 10 out of 12 publications