Bioengineered AV Grafts: They Are Finally Happening! Lawson JH, - - PowerPoint PPT Presentation

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Bioengineered AV Grafts: They Are Finally Happening!

Jeffrey H. Lawson, M.D., Ph.D.

Departments of Surgery and Pathology Duke University Medical Center Durham, North Carolina

Disclosure Information

Lawson JH, FINANCIAL DISCLOSURE: Consultant and Research Funding; Humacyte, Inc.

None of the data presented in this lecture is intended to be perceived as “claims” for the potential clinical use of the bioengineered vascular graft discussed today.

Vascular Grafts and Failure

• 40% of CABG vein grafts are occluded

at 1 year.1

• Primary patency of lower leg vein

bypass is 70% at 5 years in the best hands.2

• Significant wound issues related to vein

harvest sites (nearly 15%).3

• 1. Prevent IV. JAMA, 294(19):2446-55, 2005
• 2. Rutherford, 5th Edition, Chapter 69, pp. 1012-13, 2000
• 3. Duke Vascular Surgery NSQIP Data, 2013

Synthetic Vascular Dialysis Grafts

– Poor long-term patency

• Neointimal hyperplasia
• Stenosis
• Thrombosis
• Graft infections
• Graft wall deterioration/abuse

– DAC study indicated loss of patency in 75% of AVGs at one year1

1Dixon et al. N Engl J Med 2009;360:2191-201.

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Histology of Implanted ePTFE Grafts

Concepts and Beliefs

• Blood likes to move through tubes lined by cells
• Blood likes to move through tubes that wiggle
• Even the best veins don’t like being arteries

Bioengineered Blood Vessels

• Bioengineered blood

vessels represent a potentially unlimited source of bypass grafts

• However, in vivo

implantation studies have been marked by acute graft rupture, thrombosis and failure

Niklason, L et. al. Science 284:489-93, 1999.

• 4. Bioengineered Vessel

Without Branches

Bioengineered Blood Vessels: Created from Human Vascular Smooth Muscle Cells

• 1. Human Cells

Isolated and Banked

• 3. Decellularization

Removes Cells

• 2. Cells are Used to Culture

Bioengineered Vessels in Bioreactors

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Suture Strength (g) Burst Pressure (mmHg) HAVG 181 ± 18 (16) 3337 ± 343 (10) Human saphenous vein 196 ± 29 (7) 1599 ± 877 (7) Human internal mammary artery 138 ± 50 (6) 3196 ± 1264 (16) SEM shows fluid tight surface, with porous interior for cell infiltration. No weeping at physiologic pressures (N=31)

Kink Radius

6mm diameter, 40cm length 6mm diameter, 40cm length

Bioreactor Silicone tube through side arm PGA mesh scaffold Dacron sleeve

Bioengineered Blood Vessels: Mechanically Similar to Native Vasculature Bioengineered Blood Vessels: Matrix of Acellular Vascular Grafts Bioengineered Blood Vessels: Human Prototype Implanted into Primates (Baboon)

• Arteriovenous model, 1-6 months
• Accessible at 4 weeks, 16G needle
• Overall patency of 80% (11/14 animals),

including 5 animals patent at 6 months

Bioengineered Vessel Outflow Vein

Axillary Artery (Armpit): 3-4mm Diameter Brachial Vein (Elbow): 2-3mm Diameter

• No immunosuppression
• No increase in PRA
• No delayed hypersensitivity
• No graft calcification

Bioengineered Vessel Bioengineered Vessel Artery Bioengineered Vessel

Bioengineered Blood Vessels for AV Access: Baboon with Graft Cannulation

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Observations in Preclinical Studies (Baboon Model): Post-Implant Gross Observations of Bioengineered Blood Vessels

Pre-implant Post-implant

Investigational Bioengineered Vessel PTFE Graft

Smooth muscle Alpha Actin CD 31 (endothelial) No Cells Pre-Implant 6 Months Baboon Model

In preclinical studies, investigational bioengineered vessels:

• repopulate with vascular cells1

1Dahl et al., Sci Transl Med, 2011, 68ra9.

Investigational Bioengineered Vessels Repopulate with Host Vascular Cells and Remodel: Baboon

100µm

Collagen Type I Immunostain Pre-Implant 6 Months 6 Months Movat’s stain - Elastin

Investigational Bioengineered Vessels Repopulate with Host Vascular Cells and Remodel the Matrix

Suture Strength (g) Burst Pressure (mmHg) Bioengineered Vessel, Pre-Implant 180 ± 44 (N=12) 3415 ± 1011 (N=4) Bioengineered Vessel, Post explant 276 ± 84 (N=11) 3669 ± 1305 (N=5) P-Value (Pre- vs Post-Implant) 0.01 0.13

Little Intimal Hyperplasia in Investigational Bioengineered Vessels in Preclinical Studies

1Prichard et al., J Cardiovasc Translational Med, 2011, 674. 2Quint et al., Proc Natl Acad Sci, 2011, 9214.

Venous anastomosis in a baboon

Bioengineered Vessel

• Little foreign body reaction1
• Less mTOR activated smooth muscle proliferation than autologous vein2

ePTFE

Intimal to Medial Ratio (3 months)

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First Experience in Man

Study Design

• Open label, single arm study, 3 sites in Poland, initiated in Dec. 2012
• Upper arm arteriovenous (AV) access for hemodialysis
• End stage renal disease (ESRD) patients who are not candidates for fistula creation
• Use for dialysis from 8 weeks
• Monthly clinical and ultrasound monitoring for first 6 months
• Patients followed for up to 2 years
• 28/30 patients enrolled

Objectives

• Evaluation of safety and tolerability in dialysis patients
• Evaluation of patency and intervention rates
• Assess changes in Panel Reactive Antibody (PRA)
• 6 Month primary endpoint

Surgical Teams

University of Medicine in Lublin Uniwersytet Medyczny w Lublinie

• Prof. Tomasz Zubilewicz
• Dr. Stanislaw Przywara
• Dr. Marek Ilzecki

Regional Specialist Hospital in Wroclaw Wojewódzki Szpital Specjalistyczny we Wrocławiu

• Prof. Wojciech Witkiewicz
• Dr. Jakub Turek
• Dr. Norbert Zapotoczny

Medical University of Warsaw Akademia Medyczna Warszawie

• Prof. Jacek Szmidt
• Dr. Thomasz Jakimowicz
• Dr. Bodhan Solonynko

Study Patient Population and First Human Implant

• 28 Caucasians [17 Male, 11 Female]
• Mean Age: 60 years (Range: 30 – 73)
• Mean BMI 28 (Range: 16 – 38)
• Concomitant diseases
• Hypertension in 82%
• Diabetes in 46%
• Vascular disease in 39%

2 4 6 8 0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8 Prior Dialysis Access Procedures 8 6 4 2 Pa ents

• 4.1 ± 1.7 prior access procedures/patient

First Human Implant of an Investigational Bioengineered Vessel

Venous Anastomosis Arterial Anastomosis Vessel in Upper Arm

Initial Data on Investigational Bioengineered Vessels 100% Overall Patency

• All 28 vessels patent
• 20/28 without intervention
• No infections, no aneurysm

Secondary patency 100% Primary patency

(9 patients at 6 month follow up)

0.2 0.4 0.6 0.8 1 1 2 3 4 5 6 Survival Distribution Function Months

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Initial Data on Investigational Bioengineered Vessels

Days on Study Diameter (mm) 0 50 100 150 200 250 300 8 6 4

" " " 0" 50" 100" 150" 200" 250" 300"

No dilata on or aneurysms [N=25]

" " " " "

Days on Study Flow rate (mL/min)

Flow rates suitable for dialysis [N=25]

4000 3000 2000 1000 0 50 100 150 200 250 300

No indication of immune response

# # # # # #

10 8 6 4 2 Pre-Implant 3 Months Post-Implant % Reac vity to PRA Class I An bodies

• 0% reac vity to PRA Class 2 in pre- &

post-implant measurements [N=6] No change in PRA Class I Reac vity [N=6]

Bioengineered Vessel Bioengineered Vessel Being Used for Dialysis

Investigational Bioengineered Vessel for Dialysis

• Flow rates suitable for dialysis: >500ml/min
• 22 patients using bioengineered vessels for dialysis 3 times per week
• >800 accesses, up to 9 months experience per graft
• Grafts easy to cannulate using standard techniques
• Only one delayed hemostasis requiring intervention
• Patient had low fibrinogen levels (0.2g/L; Normal range: 2-4g/L)

Off-the-shelf bioengineered vascular grafts are possible Non immunogenic Integrate with native tissue, repopulate and remodel Post implant with increased strength and little intimal hyperplasia First-in-man pilot clinical trial underway in Poland and the US for hemodialysis access and PAD

Summary

Thank You

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8 of 28 patients lost primary patency since December 2012

• 10 patency interventions in

these 8 patients

• 8 thrombectomies (1 with

revision of anastomosis, 1 with angioplasty)

• 2 venous anastomosis

angioplasties without thrombosis

• 71% Primary unassisted patency

1 steal syndrome: cuff placed

Initial Data on Investigational Bioengineered Vessels

CURRENT OVERALL PATENCY 100%

0 1 2 3 4 5 6 7 8 9 10 11

Thrombosis Stenosis

Pa ents Dura on of Implanta on (Months)

Duke Hospital: June 5, 2013