ENDOVASCULAR DEVICE TO DECALCIFY AND REGENERATE HEART
VALVES SO A PATIENT MAY KEEP
THEIR OWN INSTEAD OF GETTING
AN IMPLANT
OUR APPROACH
#1 - Debulk calcification with dental burr on tip of
deflecting tip catheter.
#2 – Ultrasonically clean entire area.
#3 - Deliver microcurrent regeneration
signal via flexible fiberoptic probe =
recruits stem cells and differentiates them
= regenerates valve and surrounding
tissues.
#4 – If the above fails implant autologous cell
tissue engineered heart valve with key hole
surgery or percutaneously OR cell sod OR glue a
leaflet extension in place constructed of
Goal = clean & regenerate the type of calcified
valves on right to look and function like the clean
healthy valve on the far left.
STEM CELLS TO REPAIR
HEART VALVES
EMBRYONIC DEVELOPMENT OF
HEART VALVES
EMBRYONIC DEVELOPMENT OF
HEART VALVES
HOW TO MAKE A HEART VALVE: FROM EMBRYONIC DEVELOPMENT TO BIOENGINEERING OF
LIVING VALVE SUBSTITUTES
DONAL MACGROGAN1, GUILLERMO LUXÁN1, ANITA DRIESSEN-MOL2, CARLIJN BOUTEN2, FRANK
BAAIJENS2 AND JOSÉ LUIS DE LA POMPA1
Early stages of heart development. (A) Central views of the
developing mouse embryo. At E7.0, cardiac progenitors (red) have
reached the head folds and, by E7.5, two cardiac lineages can be
distinguished: the first heart field (FHF) (red) and the second heart
field (SHF) (blue). At E8.0, the FHF progenitors merge to form the
heart tube, which elongates at arterial and venous poles by the
addition of progenitor cells from the second heart field (SHF).
Between E8.0 and E9.0, the heart tube undergoes rightward looping.
(B) Central view of the E9.5 heart, which consists of four
anatomically distinct regions: atrium (At), atrioventricular canal
(AVC), ventricle (V), and the outflow tract (OFT). (C) Longitudinal
section depicting the prevalvular ECs. Two elongated cushions can
be seen in the OFT, consisting of proximal (conal cushions, purple)
and distal (truncal ridges, green) sections. The AVC has four
cushions: right lateral (rlAVC), left lateral (llAVC), superior (sAVC),
and inferior (iAVC). (Figure created from data adapted from Snarr et
al. 2008.)
US PATENT NO: 5,957,949
US Patent No: 5,957,949 – MAY 1997
Percutaneous placement valve stent
Abstract
An artificial valve stent for maintaining patent one way flow within a biological
passage is disclosed. The artificial valve includes a tubular graft having radially
compressible annular spring portions for biasing proximal and distal ends of
the graft into conforming fixed engagement with the interior surface of a
generally tubular passage. Also disclosed is a deployment catheter including
an inner catheter having a nitinol core wire, a controllable tip balloon at its the
distal end for dilation and occlusion of the passage, and a controllable graft
balloon in the vicinity of and proximal to the tip balloon for fixedly seating the
spring portions in conformance with the interior surface of the passage. A
spool apparatus for adjusting or removing an improperly placed or functioning
artificial valve, and a microembolic filter tube are usable with the deployment
catheter. The artificial valve may be completely sealed to the living tissue by
light activated biocompatible tissue adhesive between the outside of the
tubular graft and the living tissue. A method of implanting the artificial valve is
also disclosed.
Inventors : Leonhardt Howard J. (Sunrise, US), Greenan Trevor (Sunrise, US)
Published Assignee : WORLD MEDICAL MANUFACTURING CORP. (Sunrise, US)
US PATENT NO: 5,957,949
Leonhardt et al US Patent No: 5,957,949 –
MAY 1997 (prototype 1988)
Percutaneous placement valve stent
17 claims highlights
 Light activated foam cuff with tissue adhesive
packets. Light heats up and causes foam cuff
to grow like a marshmellow in a microwave.
 Cell in-growth encouraging foam cuff.
 Removal and repositioning system.
 Nitinol adaptive conformace sealing stent.
 CIP multi-stage 8FR delivery – piece by
piece.
PATENTED MULTI-STAGE DESIGN
TO REDUCE ENTRY PROFILE
U.S. Patent 6572645 B2 – Priority Feb 1998
Inventor
Howard J. Leonhardt
Delivery system for development and endovascular
assembly of a multi-stage stented graft
ABSTRACT
A multi-stage stent graft for implantation into a blood
vessel is disclosed. Each stage or layer may comprise
radially compressible spring stents with or without a
fabric covering, or may comprise a foamed tube. The
various stages or layers may also have an adhesive
coated thereon. The multi-stage stented graft and the
adhesive coatings provide a surface for the ingrowth
of cells and promote healing. Also disclosed is a
coaxial delivery system for the delivery and
endovascular assembly of the multi-stage stented
graft during one trip into the vasculature.
STEP 1 = Decalcify
with dental burr on tip
of deflecting tip
catheter
BURRS FOR DEBULKING
CALCIFICATION ON CATHETER TIP
BULK DECALCIFY
WITH BURR
FLEXIBLE MICROSCOPE
EXPLORES DEEPLY
HIDDEN CELLS
CELLVIZIO TECHNOLOGY MICROSCOPE ON A CATHETER TIP
Step 2 = Ultrasonic
cleaning.
ULTRASONIC CLEANING
DEVICE
Step 3 = Deliver regenerative
microcurrent to valve via
flexible optical fiber. Causes
SDF-1 release which recruits
stem cells and separate
signal differentiates those
cells into valve tissue.
How does microcurrent energy repair heart
valve tissue? …
#1 - Causes SDF-1 release from targeted
tissue which homes stem cells to
damaged tissue. Treats whole valve and
surrounding tissues.
#2 – Differentiates recruited cells into
healthy tissue.
#3 – Builds heart valves the way they are
built in first place just like embryos.
THE FUTURE IS NOW: WIRELESS
MICRO CURRENT DIRECTED STEM
CELL REGENERATION
STRICTLY PRIVATE AND CONFIDENTIAL
26
MICROCURRENT REGENERATIVE SIGNAL
DELIVERED TO DISEASED HEART VALVE VIA
FLEXIBLE FIBER OPTICS
FLEXIBLE FIBER PROBE FOR
MICROCURRENT DELIVERY
LOW PROFILE MICROCURRENT
DELIVERY FOR REGENERATION
THE REMODELING OF CARDIOVASCULAR
BIOPROSTHESES UNDER INFLUENCE OF STEM
CELL HOMING SIGNAL PATHWAYS.
Biomaterials. 2010 Jan;31(1):20-8. doi: 10.1016/j.biomaterials.2009.09.016. Epub 2009 Sep 22. De Visscher G1,
Lebacq A, Mesure L, Blockx H, Vranken I, Plusquin R, Meuris B, Herregods MC, Van Oosterwyck H, Flameng W.
Abstract
Optimizing current heart valve replacement strategies by creating living prostheses
is a necessity to alleviate complications with current bioprosthetic devices such as
calcification and degeneration. Regenerative medicine, mostly in vitro tissue
engineering, is the forerunner of this optimization search, yet here we show the
functionality of an in vivo alternative making use of 2 homing axes for stem cells. In
rats we studied the signaling pathways of stem cells on implanted bioprosthetic
tissue (photooxidized bovine pericardium (POP)), by gene and protein expression
analysis. We found that SDF-1alpha/CXCR4 and FN/VLA4 homing
axes play a role. When we implanted vascular grafts impregnated
with SDF-1alpha and/or FN as carotid artery interpositions,
primitive cells were attracted from the circulation. Next, bioprosthetic
heart valves, constructed from POP impregnated with SDF-1alpha and/or FN, were
implanted in pulmonary position. As shown by CD90, CD34 and CD117
immunofluorescent staining they became completely recellularized after 5 months,
had a normal function and biomechanical properties and specifically the
combination of SDF-1alpha and FN had an optimal valve-cell phenotype.
Step 4 – Implant
Autologous Cell Valve
Mounted in Stent OR
cell sod valve OR glue
in place Autologous
Cell create Valve
Leaftets
Minimally-Invasive Implantation of Living
Tissue Engineered Heart Valves
A Comprehensive Approach From
Autologous Vascular Cells to Stem Cells
Dörthe Schmidt, MD, PhD?,†,‡; Petra E. Dijkman, MSc§; Anita Driessen-Mol,
PhD§; Rene Stenger, BSc‡; Christine Mariani, MSc?; Arja Puolakka, MSc?;
Marja Rissanen, LicTech?; Thorsten Deichmann, DiplIng¶; Bernhard
Odermatt, MD#; Benedikt Weber, MD?,†,‡; Maximilian Y. Emmert, MD?,†,‡;
Gregor Zund, MD‡; Frank P.T. Baaijens, PhD§; Simon P. Hoerstrup, MD,
PhD?,†,‡
[+] Author Information
J Am Coll Cardiol. 2010;56(6):510-520. doi:10.1016/j.jacc.2010.04.024
DATA SUPPORTING STEM CELL
REPAIR OF HEART VALVES IS
BUILDING
Injectable living marrow stromal cellbased autologous tissue engineered
heart valves: first experiences with a
one-step intervention in primates
Benedikt Weber , Jacques Scherman , Maximilian Y. Emmert ,
Juerg Gruenenfelder , Renier Verbeek , Mona Bracher , Melanie
Black , Jeroen Kortsmit , Thomas Franz , Roman Schoenauer ,
Laura Baumgartner , Chad Brokopp , Irina Agarkova , Petra
Wolint , Gregor Zund , Volkmar Falk , Peter Zilla , Simon P.
Hoerstrup
DOI: http://dx.doi.org/10.1093/eurheartj/ehr059 2830-2840 First
published online: 17 March 2011
DATA SUPPORTING STEM CELL
REPAIR OF HEART VALVES IS
BUILDING
Valvular Heart Disease – CIRCULATION
From Stem Cells to Viable Autologous
Semilunar Heart Valve
Fraser W.H. Sutherland, FRCS; Tjorvi E. Perry, MD; Ying Yu,
PhD; Megan C. Sherwood, MD; Elena Rabkin, MD, PhD; Yutaka
Masuda, MD, PhD; G. Alejandra Garcia, MD; Dawn L. McLellan,
MD; George C. Engelmayr Jr, PhD; Michael S. Sacks, PhD;
Frederick J. Schoen, MD, PhD; John E. Mayer Jr, MD
Regenerative Medicine Approach to Heart
Valve Replacement
Stephen F. Badylak, DVM, MD, PhD
ADIPOSE STEM CELL COLLECTION
KIT
Produced according
to cGMP
Each Laboratory Kit
includes:
• A vial of lyophilized
“Adipolase” which
consists of a clinical
grade collagenase
• consumables necessary
to isolate regenerative
stem cells
THE SWISS EXPERIENCE
Pre-Clinical Research | August 2012
Stem Cell–Based Transcatheter Aortic
Valve Implantation
First Experiences in a Pre-Clinical
Model Maximilian Y. Emmert, MD?; Benedikt Weber, MD?; Petra Wolint?; Luc
Behr, VDM, PhD¶; Sebastien Sammut, PhD?; Thomas Frauenfelder, MD§; Laura Frese,
PhD?; Jacques Scherman, MD‡; Chad E. Brokopp, PhD?; Christian Templin, MD?; Jürg
Grünenfelder, MD†; Gregor Zünd, MD?; Volkmar Falk, MD‡; Simon P. Hoerstrup, MD,
PhD?
Swiss Center for Regenerative Medicine, University
and University Hospital Zurich, Zurich, Switzerland
J Am Coll Cardiol Intv. 2012;5(8):874-883.
doi:10.1016/j.jcin.2012.04.010
THE SWISS EXPERIENCE
Objectives This study sought to investigate the combination of
transcatheter aortic valve implantation and a novel concept of
stem cell-based, tissue-engineered heart valves (TEHV)
comprising minimally invasive techniques for both cell harvest and
valve delivery.
Methods Within a 1-step intervention, trileaflet TEHV, generated
from biodegradable synthetic scaffolds, were integrated into selfexpanding nitinol stents, seeded with autologous bone marrow
mononuclear cells, crimped and transapically delivered into adult
sheep (n = 12). Planned follow-up was 4 h (Group A, n = 4), 48 h
(Group B, n = 5) or 1 and 2 weeks (Group C, n = 3). TEHV
functionality was assessed by fluoroscopy, echocardiography, and
computed tomography. Post-mortem analysis was performed
using histology, extracellular matrix analysis, and electron
microscopy.
THE SWISS EXPERIENCE
Results Transapical implantation of TEHV was successful in
all animals (n = 12). Follow-up was complete in all animals of
Group A, three-fifths of Group B, and two-thirds of Group C (1
week, n = 1; 2 weeks, n = 1). Fluoroscopy and
echocardiography displayed TEHV functionality demonstrating
adequate leaflet mobility and coaptation. TEHV showed intact
leaflet structures with well-defined cusps without signs of
thrombus formation or structural damage. Histology and
extracellular matrix displayed a high cellularity indicative for an
early cellular remodeling and in-growth after 2 weeks.
Conclusions We demonstrate the principal feasibility of a
transcatheter, stem cell–based TEHV implantation into the
aortic valve position within a 1-step intervention. Its long-term
functionality proven, a stem cell–based TEHV approach may
represent a next-generation heart valve concept.
BASICS OF STEM CELL DERIVED
HEART VALVE PROCEDURE
THE SWISS EXPERIENCE
THE SWISS EXPERIENCE
Stem Cell–Based, TEHV Implantation Into the Aortic
Valve Position via a Transcatheter, 1-Step Interventional
Approach
Bone marrow is aspirated from the sternum into a
heparinized syringe (1) and bone marrow mononuclear cells
(BMMC) are obtained by centrifuging the samples on a
histopaque density gradient (2). The BMMC are seeded
onto the stented heart valve scaffolds using fibrin as a cell
carrier (3). Thereafter, the tissue-engineered heart valve
(TEHV) is loaded into the delivery device by crimping the
outer diameter down to 8 mm and transapically delivered
(4). The mean duration of the entire procedure, starting
from cell harvest until TEHV-implantation takes
approximately 2 h.
THE SWISS EXPERIENCE
THE SWISS EXPERIENCE
Explant Macroscopy of TEHV
Explanted tissue-engineered heart valves (TEHV)
displayed intact leaflet structures with well-defined
cusps and sufficient coaptation, without signs of
thrombus formation, thickening, shrinking, or
structural damage from the lower view (A and inset)
and the upper view (B). The TEHV harvested at 1 and
2 weeks after implantation appeared to be well
integrated into the surrounding tissue by complete
tissue covering of the stent-frame (C).
THE SWISS EXPERIENCE
THE SWISS EXPERIENCE
Histological Analysis of TEHV Explants
On histology, acute explants showed clear cellular
infiltrates and fibrin formation in hematoxylin and
eosin staining (A to D) (magnification 5× and 10×).
Interestingly, this cellularity only slightly increased in
the tissues of the 24-h explants (images not shown),
whereas all later explant stages at 1 week and 2
weeks showed a clearly increased cellularity (E to L)
(magnification 5× and 10×). TEHV = tissue-engineered
heart valve(s).
THE SWISS EXPERIENCE
THE SWISS EXPERIENCE
Performance of TEHV and Echocardiography
Findings
Tissue-engineered heart valve (TEHV) functionality
and mobility was controlled via epicardial and
transesophageal echocardiography. TEHV
tolerated the loading pressure of the systemic
circulation adequately and demonstrated a
sufficient coaptation (A, B, and insets). TEHV
functionality and absence of regurgitation was
confirmed in the 2-dimensional color mode (C, D,
and insets) and in the 3-dimensional mode
demonstrating adequate leaflet mobility (E to G,
and insets). See Online Videos 2A, 2B, and 2C.
AUTOLOGOUS CELLS +
SCAFFOLD PRODUCED HEART
VALVE
TISSUE ENGINEERED VALVE
TISSUE ENGINEERED VALVE
TISSUE ENGINEERED VALVE
DELIVERY
VIEW OF EXPLANTED TISSUED
ENGINEERED VALVES
CELL SODDING AND SUTURING
CATHETER
COMPARABLE CONCEPT OF HOW
TO GLUE A NEW TISSUE
ENGINEERED LEAFLET IN PLACE
EXAMPLES OF
MICROCURRENT HEALING
Over 50 studies have been completed
documenting the healing ability of
microcurrent.
The Leonhardt team has received two
U.S. patents with many more pending.
Major patent claims include specific
program to cause any tissue to release
stem cell homing signal and control of
differentiation.
510KD MICROCURRENT
STIMULATORS FOR HEALING
STRICTLY PRIVATE AND CONFIDENTIAL
56
THE FUTURE IS NOW: WIRELESS
MICRO CURRENT DIRECTED STEM
CELL REGENERATION
STRICTLY PRIVATE AND CONFIDENTIAL
57
WIRELESS
MICROCURRENT
HEALING
PAPER ON WIRELESS
MICRO CURRENT
STIMULATION
STRICTLY PRIVATE AND CONFIDENTIAL
59
Microcurrent Treatment 95% Reduction of
Wound Scar Size @ 8 Weeks
47 Patient Clinical Study – Germany & Switzerland –
Published International Wound Journal ISSN 1742-4801
2014
CARDIOBRIDGE CIRCULATORY
ASSIST PUMP
STRICTLY PRIVATE AND CONFIDENTIAL
61
Procyrion and Cardiobridge
ACCESSORY CIRCULATORY
ASSIST DEVICES TO
RELIEVE HEART WORK
LOAD AND IMPROVE
PERFUSION IN LIMBS –
RECOMMENDED FOR ALL
HEART, VALVE AND LIMB
REGENERATION
PROCEDURES
PROCYRION TEMPORARY
AORTIC PLACED
CIRCULATORY ASSIST
STRICTLY PRIVATE AND CONFIDENTIAL
63
ADVANCED ARTERY
REPAIR METHOD
Athrectomy followed by adventia
delivery of autologous endothelial
progenitor cells (derived from fat
tissue) – EndoCell – for artery
repairing. Regrows healthy
endothelium lining in vessel.
ATHRECTOMY FOLLOWED BY ENDOTHELIUM
ADVENTIA RE-LINING WITH INJECTED EPC’S
STRICTLY PRIVATE AND CONFIDENTIAL
65