Regenerative Strategies for Vascular and Lung Tissues. Laura E Niklason MD, PhD

Transcription

1 Regenerative Strategies for Vascular and Lung Tissues Laura E Niklason MD, PhD

2 Disclosure: Some of this work in this presentation is from Humacyte Inc. Niklason is a founder of Humacyte, and holds stock in the company.

3 Composition, Design Requirements for Arteries: - Must have adequate mechanical strength: 3 billion stress cycles over our lifetimes - Must prevent blood clotting functions of the endothelium, heparin, nitric oxide - If cellular, must be autologous. The Grand Challenge is the off-the-shelf, small caliber vascular graft

4 Rupture strengths of native arteries > 2,000 mm Hg

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6 A blood vessel model constructed from collagen and cultured vascular cells Weinberg & Bell, Science 1986; 231: 397.

7 Transplantation of a tissue-engineered pulmonary artery Shin oka, Imai, Ikada, New England Journal of Medicine 2001; 344: 532.

8 Late-term results of tissue-engineered vascular grafts in humans. J. Thoracic Cardiovascular Surgery 2101; 139: 431. Extracardiac cavo-pulmonary shunts Pediatric patients, low pressure system. Autologous marrow- derived cells on a biodegradable polymer scaffold culture time of hours.

9 Technology insight: The evolution of tissue engineered vascular grafts, from research to practice Nature Clinical Practice 2007; 4: 389. Revolutionary dialysis graft in adults. Drawbacks: cells from the patient; long culture time (6 months or more)

10 Mechanically strong vessels that do not require cells from the patient: Rupture > 3,000 mm Hg

11 Readily available tissue engineered vascular grafts, Science Translational Medicine 2011; 2;3(68). Overall patency in baboons > 80%, follow-up 1 to 6 months; grafts are off-the-shelf.

12 Allogeneic, acellular arteries do they meet design criteria? - Must have adequate mechanical strength - Must prevent blood clotting - If cellular, must be autologous. At larger calibers (eg. > 6 mm, high flow rates), presence of anti-coagulation provided by endothelium is not critical. However, for small calibers the Grand Challenge anti-coagulation is essential.

13 Ongoing work covalent chemistry on the graft lumen to mimic some of the actions of native endothelial cells..... all with the goal of producing an artery off-the-shelf...

14 Human Lung is a tremendously complex organ regeneration of the solid organ presents new challenges: - 23 generations of airway branching - 70 square meters surface area for gas exchange million air sacs, each 200 microns in size - Blood-gas barrier is protein membrane 50 nm thick

15 First attempt at human lung replacement the polio epidemic :

16 Attempts at intra-vascular oxygenation limited by low surface areas, thrombosis around the capillary tubes :

17 Functional Lung design criteria: Adequate surface area for O 2 /CO 2 exchange Maintain barrier function between blood and air Proper mechanics not emphysematous or fibrotic Cellular components must be autologous Grand Challenge Produce an autologous organ that can support long-term gas exchange, without rejection.

18 Lung matrix has anatomic complexity retained - Vascular architecture Air-sac architecture

19 Paradigm for lung regeneration: eventually, cells to populate the matrix will come from stem cells that we create for each patient, from a small biopsy of skin

20 Native Re-populated Native Decell Engineered

21 Implantation of engineered lung into rat recipient - Petersen, et al, Science 2010

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24 To approach the challenge of human lung regeneration, we need a source of pulmonary epithelial cells - Yamanaka 2006, 2008

25 Differentiation of human ips into pulmonary epithelium: A Trophic Factors SB431542(10µM) Activin A NOGGIN (200ng/ml) EGF(10ng/ml),FGF10 (10ng/ml) (100ng/ml) KGF (10ng/ml),WNT3a (100ng/ml) 21 ips Definitive endoderm Anterior foregut endoderm Differentiation Alveolar progenitor Maturation days AETII

26 Human lung bioreactor development stepping stone for meeting the grand challenge :

27 Bioreactor supports organ growth and survival, and provides for ventilation of liquid medium (or air) similar to native:

28 Outstanding Laboratory Group: Liqiong Gui PhD Sumati Sundaram PhD Julio Mendez PhD Jenna Balistrini PhD Mahboobe Ghaedi PhD Ashley Gard BS Elizabeth Calle BS Liping Zhao MS - Sam Raredon BSE - Thomas Petersen MD, PhD - Shannon Dahl PhD - Juliana Blum PhD - Justin Strader BSE - Heather Prichard PhD Key Collaborators: Jeffrey Lawson MD, PhD Alan Kypson MD Tai Yi MD Erica Herzog MD, PhD