biomaterials for the treatment of myocardial · pdf filebiomaterials for the treatment of ......

Journal of the American College of Cardiology Vol. 58, No. 25, 2011© 2011 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00

STATE-OF-THE-ART PAPER

Biomaterials for theTreatment of Myocardial InfarctionA 5-Year Update

Aboli A. Rane, MS, Karen L. Christman, PHD

La Jolla, California

The first review on biomaterials for the treatment of myocardial infarction (MI) was written in 2006. In the last5 years, the general approaches for biomaterial treatment of MI and subsequent left ventricular remodeling re-main the same, namely, left ventricular restraints, epicardial patches, and injectable therapies. Nonetheless,there have been significant developments in this field, including advancement of biomaterial therapies to largeanimal pre-clinical studies and, more recently, to clinical trials. This review focuses on the progress made in thefield of cardiac biomaterial treatments for MI over the last 5 years. (J Am Coll Cardiol 2011;58:2615–29)© 2011 by the American College of Cardiology Foundation

Published by Elsevier Inc. doi:10.1016/j.jacc.2011.11.001

With myocardial infarction (MI) as a major contributor tocardiovascular disease, the leading cause of death in theWestern world, there is a rising need for novel therapies fortreatment of post-MI negative left ventricular (LV) remod-eling. Although LV remodeling post-MI can be beneficialat first, over time, this compensatory mechanism can bemaladaptive, ultimately leading to heart failure (1). Cur-rently, pharmacologics, total heart transplantation, and LVassist devices are the only widespread forms of remedy.Cellular transplantation has been explored for almost 2decades now, with numerous ongoing clinical trials; how-ever, significant gains in cardiac function have yet to berealized. Nonetheless, over the last decade or so, biomaterialtechnologies have emerged and have shown great promise aspotential treatments for MI.

Biomaterials for the treatment of MI were first reviewed5 years ago (2). Over the last 5 years, the general biomaterialapproaches to treatment of MI have remained the same: LVrestraints, cardiac patches, and injectable approaches (Fig. 1).Although the numbers are small, we are now beginning tosee clinical trials with cardiac patches and, most recently,injectable biomaterials, demonstrating that the biomaterialapproach to MI treatment is moving forward at a rapid pace.This review focuses on the advancements made over the last5 years in the use of biomaterials for the treatment of MI(Tables 1 and 2). Only biomaterials that have been utilizedfor the treatment of MI in vivo are discussed.

From the Department of Bioengineering, University of California-San Diego, LaJolla, California. Ms. Rane has reported that she has no relationships relevant to thecontents of this paper to disclose. Dr. Christman is the cofounder of Ventrix Inc.D. Geoffrey Vince, PhD, served as the Guest Editor for this paper.

Manuscript received August 16, 2011; revised manuscript received October 28,2011, accepted November 1, 2011.

LV Restraints

Previously, numerous studies evaluated the use of biomate-rial supports to constrain the LV. In the last 5 years, oneadvancement is Paracor’s HeartNet LV support system—anitinol mesh weave (Paracor Medical, Sunnyvale, Califor-nia) that is placed around the ventricles—which has beenshown to reduce LV end-diastolic (ED) and end-systolic(ES) volume indices and LV mass in an ovine MI model (3),and reduce ED volume and increase mean arterial pressureand LV pressures in a canine chronic heart failure model (4).Paracor has undergone an initial clinical feasibility study (5),and is in their pivotal trial titled the PEERLESS-HF(Prospective Evaluation of Elastic Restraint to LESSen theEffects of Heart Failure). Although the outcomes of thistrial are currently unknown, the few studies on LV restraintsindicate declining interest, possibly due to the invasiveprocedure required for this approach.

Cardiac Patches

Initially, cardiac patches involved the use of biomaterialscaffolds to enhance cell delivery and, more recently, havebeen used as an acellular therapy. It is thought that themicroenvironment and architecture provided by such ascaffold can support cellular differentiation and organiza-tion, and prevent anoikis (6). Application of various bioma-terials with a variety of cell types has shown an improvementin cardiac function in small animals. Nonetheless, 1 majordrawback with this method remains the inability to generatepatches with sizable thickness due to diffusion limitations(2,6). In the last 5 years, many different scaffolds have beenexamined in vitro for such applications (6); however, only in
vivo work is discussed in the following text.

is(ipmdH

pdc

pIsfiDsMwmfiaabh1ti

o

2616 Rane and Christman JACC Vol. 58, No. 25, 2011Biomaterials for the Treatment of MI December 13/20, 2011:2615–29

Of the different materials usedfor the fabrication of cardiacpatches in recent years, collagen,the predominant protein in theextracellular matrix, has beenused extensively, alone and withcells. Callegari et al. (7) showedthat application of a collagensponge to a rat cryoinjury modelimmediately post-injury led toincreased angiogenesis, com-pared with the control, 15 and 60days post-implantation of thepatch. Additionally, delivery ofhuman bone marrow– derivedCD133� cells (4 � 106 cells)with a collagen scaffold increasedthe number of vessels in a ratcryoinjury model; however, therewas no significant differentiation

nto cardiomyocytes (8). Similarly, application of a collagencaffold seeded with human mesenchymal stem cellsMSCs) (1 � 106 cells) immediately post-infarction resultedn a 30% increase in fractional shortening (FS) in theatch-treated group compared with the control in a rodentodel (9). Hamdi et al. (10) compared intramyocardial

elivery of cells with a cardiac patch–based approach.uman skeletal myoblasts (5 � 106 cells), control medium,

a bilayer myoblast cell sheet, or a myoblast-seeded collagensponge was injected or implanted at the site of infarction, 4weeks post-MI. Animals that received the cell sheet andseeded cell scaffold showed significant improvement inejection fraction (EF) and increased vessel density comparedwith the control, 1 month post-implantation. In the MAGNUM(Myocardial Assistance by Grafting a New BioartificialUpgraded Myocardium) phase 1 clinical trial, a collagentype I patch seeded with bone marrow cells was applied on10 patients that had coronary artery bypass graft and

Abbreviationsand Acronyms

bFGF � basic fibroblastgrowth factor

ED � end-diastolic

EF � ejection fraction

ES � end-systolic

FS � fractional shortening

LV � left ventricle

MI � myocardial infarction

MSC � mesenchymal stemcell

PEG � poly(ethyleneglycol)

SIS � small intestinalsubmucosa

VEGF � vascularendothelial growth factor

Figure 1 Biomaterial Approaches to Treatment of MI

There are 3 strategies currently being examined for the treatment of myocardial inmaterials. Cardiac patches and injectable materials can be either used as acellulacules (C and F).

intrainfarct implantation of autologous bone marrow cells(Fig. 2). Both the combined approach of cell injection anda cardiac patch as well as the cell injection alone showed animprovement in EF at a 10 � 3.5 months follow-upcompared with the baseline measurement 1 week beforecoronary artery bypass. However, LV ED volume and scarthickness were improved in the patients that received acell-seeded collagen patch combined with cellular injectioncompared with those receiving the intrainfarct cell injectionalone (11). Similarly, an improvement in EF was seen in amouse MI model upon application of a collagen patchseeded with human umbilical cord mononuclear cells (5 �106 cells) along with an injection of the same cell type (5 �106 cells) or by the injection of the cells alone 45 days

ost-treatment when compared with the baseline, whereaseterioration of function was seen in the scaffold-only andontrol groups (12).

Giraud et al. (13) showed improvement in FS, 4 weeksost-treatment, using a combination patch of collagen type, Matrigel (BD Biosciences, San Jose, California), and ratkeletal muscle cells adhered on the surface of the heart withbrin glue, 2 weeks post-MI in a rodent model. Similarly,vir et al. (14) constructed a patch by seeding an alginate

caffold with neonatal cardiomyocytes (7 � 107 cells/cm3) inatrigel and pro-survival and angiogenic factors. The patch

as cultured in the rat omentum for 7 days to promoteaturation of vasculature and then transplanted into in-

arcted rats 1 week post-infarction. At 28 days post-mplantation, this pre-vascularized patch showed structuralnd electrical integration with the host myocardium as wells preservation of FS and fractional area change. Anotherio-derived scaffold, fibrin, has also been seeded withuman embryonic stem cell–derived endothelial cells (2 �06 cells) and smooth muscle cells (2 � 106 cells). Implan-ation in a porcine model immediately post-MI resulted inmproved EF at 7 days and persisted until 4 weeks (15).

A recent development has been the use of decellularizedrgans for the creation of cardiac patches representing the

n (MI): left ventricular restraints (not shown), cardiac patches, and injectable bio-folds (A and D), or delivery vehicles for cells (B and E) and/or biological mole-

farctior scaf

2617JACC Vol. 58, No. 25, 2011 Rane and ChristmanDecember 13/20, 2011:2615–29 Biomaterials for the Treatment of MI

complex milieu of the native extracellular matrix. Ott et al.(16) first demonstrated the ability to decellularize themyocardium. Godier-Furnémont et al. (17) seeded humanmesenchymal progenitor cells (1 � 106 cells) in fibrin on adecellularized human myocardial sheet. Implantation of thescaffold preserved FS and LV diameter, as well as anenhanced vascular network, by secretion of paracrine factorsand migration of the MSCs into the damaged myocardium4 weeks post-treatment in a rat MI model. Similarly,decellularized small intestinal submucosa (SIS) itself orseeded with MSCs in a rabbit MI model 4 weeks post-treatment led to an improvement in LV ES and EDdiameters and EF compared with the control. Furthermore,animals treated with the MSC-seeded SIS had a signifi-cantly greater improvement in EF compared with theanimals treated with the SIS alone (18). Likewise, a patchmade with a sliced decellularized pericardial tissue scaffoldinserted with multilayered MSCs was used to replace theinfarcted myocardium in a rodent model, and resulted ingreater FS, higher LV ES pressure, and lower LV EDpressure when compared with the control (19). Thoughthere are only limited studies using an organ-derived scaf-fold in the heart to date, this will likely increase given therapidly expanding use of decellularized scaffolds in tissueengineering.

Along with biologically derived materials, a number ofsynthetic materials have been explored. Fujimoto et al. (20)showed that application of an elastic biodegradable polyesterurethane urea scaffold over a 2-week rodent infarct led to anincrease in regional fractional area change, wall thickness, andcapillary density compared with the control MI group 8 weekspost-implantation. Siepe et al. (21,22) generated a scaffold byseeding rat skeletal myoblasts on a highly porous polyurethanescaffold. After implantation, 2 weeks post-MI, in a rat model,there was evidence that both the muscle grafts and the injectionof skeletal myoblasts alone led to improved contractile functionand increased EF 4 weeks post-implantation, compared withthe acellular scaffold group and the control. In a follow-uplong-term study, prevention of heart failure was seen up to 9months; however, this diminished by 12 months, indicatingsuch a therapeutic approach may have transient benefit (23).Piao et al. (24) implanted biodegradable poly(glycolide-co-caprolactone) with or without bone marrow–derived mononu-clear cells 7 days post-infarction in a rat. Four weeks post-implantation, there was improved FS, LV ED pressure, andLV ED and ES diameters in both scaffold groups comparedwith the sham-operated group. Another study compared theeffectiveness of direct cell injection versus a cardiac patch–based approach. MSCs (1 � 106 cells) were directly trans-planted into the border of a cryoinjury infarct or seeded ontopoly(lactide-co-�-caprolactone) and implanted over the in-farct area 10 days post-MI. EF increased by 23% and theinfarct area decreased by 29% in the polymer � MSC groupcompared with saline and the acellular scaffold, 4 weekspost-treatment. Similar results were seen in the MSC-only
group (25).
Injectable Biomaterials

Over the last 5 years, there has been extensive growth in thefield of injectable biomaterials for treating MI. Thesematerials have been injected alone or used as deliveryvehicles for cells and/or biological moieties. Injectable ma-terials have shown positive results such as improvement incardiac function, reduction of infarct size, and increase inneovascularization. It is now well established that delivery ofcells in a biomaterial can improve cellular retention andviability. Given the promise of this approach, materials haveadvanced to large-animal pre-clinical models and even earlyclinical trial stage (26). Most notably, materials such asalginate and myocardial matrix have gelation properties thatfacilitate percutaneous delivery into the myocardium (27–29),alleviating the need for invasive procedures required for theapplication of LV restraints and cardiac patches.

Proof of concept for the ability of injectable biomaterialsalone to preserve cardiac function post-MI and to improvecell transplant survival was first demonstrated with fibrin ina rat ischemia-reperfusion model (30,31). This initial studyutilized skeletal myoblasts, and these results have since beenconfirmed with a variety of cell types such as bone marrowcells (32), marrow-derived cardiac stem cells (33), andadipose-derived stem cells (34,35). In some studies, fibrinalone caused improvement in function similar to that ofinjection of fibrin with cells, whereas in others cases, anenhancement of cardiac function was seen by adding cells tothe biomaterial. The reason for the discrepancy is unclear,but it could be due to the difference in the rat MI modelsused. Injection of cells may provide additional value com-pared with acellular injection; however, to date, manystudies show similar improvements in cardiac function witha biomaterial alone. Basic fibroblast growth factor (bFGF)in fibrin (36), hepatocyte growth factor in a pegylated fibrin(37), and transforming growth factor �-1 in poly(lactic-co-glycolic acid) microspheres and bone marrow mononu-clear cells in a fibrin gel (38) have also been explored fortreatment of MI. In a pig model, direct microinjections of afibrin-alginate composite in the infarct, 1 week post-MIpreserved wall thickness and decreased infarct expansion 7days post-injection (39). One potential concern with fibrin,however, is the 2-component system made of fibrinogen andthrombin, making minimally invasive delivery a challenge.

The pivotal work done in 2005 by Leor et al. (40) haspaved the way for the use of alginate as a scaffold formyocardial tissue engineering for injection alone or as ascaffold for growth factor or cell delivery. In the last 5 years,major progress has been made with this seaweed-derivedpolysaccharide. Landa et al. (41) showed that injection ofalginate at 1 week in a rat MI resulted in increased scarthickness and improved LV ES and ED area compared withsaline 2 months post-injection. These results were similar orsuperior to injection of neonatal cardiomyocytes. At 6 weekspost-injection, the biomaterial was degraded, thus the
increase in wall thickness was potentially due to infiltrating

5-Year Update on Biomaterials for the Treatment of MITable 1 5-Year Update on Biomaterials for the Treatment of MI

2006–2011 Prior to 2006*

Material Transplantation Model Ref. # Transplantation Model

LV restraints

Polypropylene — — — Alone Sheep

Polyester Alone Sheep (84) Alone Dog, sheep, human

Nitinol Alone Dog, sheep, human (3–5) — —

Cardiac patch

Gelatin — — — Alonew/Fetal CM

Rat

Alginate — — — w/Fetal CM Rat

Poly(glycolide)/poly(lactide) — — — w/Dermal fibroblasts Mouse

PTFE, PLA mesh, collagen type Iand matrigel

— — — Alonew/Bone marrow–derived mesenchymal progenitor cells

Rat

PTFE — — — Alone Pig

Collagen type I and Matrigel w/SkM Rat (13) w/Neonatal CM Rat

Collagen type I Alonew/BMC, HUCBCs, hBMC CD133�, hMSC, hSkM

Rat, human, mouse (7–12) Alonew/ESC

Rat

Alginate and Matrigel w/SDF-1, IGF-1 and VEGFw/Neonatal CM � SDF-1, IGF-1 and VEGF

Rat (14) — —

Chitosan — — — Alone w/FGF-2 Rabbit

Fibrin Alonew/hESc-derived ECs and hESC-derived SMCs

Pig (15) — —

Polyurethane Alonew/SkM

Rat (21,22) — —

Polyester urethane urea Alone Rat (20) — —

Poly(glycolide-co-caprolactone) Alonew/BMMNC

Rat (24) — —

Poly(lactide-co-�-caprolactone) Alonew/MSCs

Rat (25) — —

Decellularized myocardium/fibrin w/Mesenchymal progenitor cells Rat (17) — —

Small intestinal submucosa Alonew/MSCs

Rabbit (18) — —

Pericardium w/MSCs Rat (19) — —

Urinary bladder matrix — — — Alone Pig

Injectable biomaterials

Fibrin Alonew/BMCs, ASCs, MCSCs, BMMNCsw/bFGF, HGF, TGF�-1

Mouse, rat, dog (32–38) Alonew/SkM, BMMNCsw/Pleiotrophin plasmid

Rat, sheep

Alginate Alone, RGD modified, RGD� YIGSR modified,RGE modified

w/VEGF, PDGF-BB, IGF-1, HGFw/hMSCsw/Polypyrrole

Rat, pig, human (26,29,41–47) Alone Rat

Fibrin -Alginate Alone Pig (39) — —

Continued on next page

2618Rane

andChristm

anJACC

Vol.58,No.25,2011Biom

aterialsfor

theTreatm

entof

MI

December13/20,2011:2615–29

ContinuedTable 1 Continued

2006–2011 Prior to 2006*

Material Transplantation Model Ref. # Transplantation Model

Chitosan Alonew/ESCsw/bFGF

Rat (54–56) — —

Gelatin Alonew/bFGF

Rat, dog (57,58) w/bFGF Rat

Collagen — — — Alonew/BMCs

Rat, pig

Matrigel Alonew/hESC derived CMsw/pro-survival factors

Rat (59,60) Alonew/ESCs

Mouse, rat

Collagen type I and Matrigel — — — Alonew/Neonatal CMs

Rat

Small intestinal matrix Alone Mouse, rat (48,49) — —

Myocardial matrix Alone Rat, pig (28,51) — —

Pericardial matrix Alone Rat (52) — —

Hyaluronic acid Alone Rat, sheep (76,77) — —

Self-assembling peptides Alonew/SkM � PDGF-BB, BMMNCsw/IGF-1, PDGF-BB, FGF-2

Rat, pig (78–81) Alonew/Neonatal CMw/PDGF-BB

Mouse, rat

Calcium hydroxyapatite Alone Sheep (61,62) — —

PEG based Alonew/BMSC, hESC � thymosin �4w/VEGF, thymosin �4, erythropoietin

Rat, rabbit (63,67,68,70,71,74,75) — —

PNIPAAm based Alonew/BMMNCs, BMSCw/bFBF

Rat, rabbit (64–66,69,72) — —

This table is modified in part from Christman and Lee (2). *All references for studies prior to 2006 can be found in Christman and Lee (2).ASC � adipose-derived stem cell; bFGF � basic fibroblast growth factor; BMC � bone marrow cell; BMMNC � bone marrow–derived mononuclear cell; BMSC � bone marrow–derived stem cell; CM � cardiomyocyte; EC �endothelial cell; ESC � embryonic stem cell; FGF �

fibroblast growth factor; HGF � hepatocyte growth factor; HUCBC � human umbilical cord blood mononuclear cell; HUVEC � human umbilical vein endothelial cell; IGF � insulin-like growth factor; MCSC � marrow-derived cardiac stem cell; MSC � mesenchymal stem cell;PCL � polycaprolactone; PDGF � platelet-derived growth factor; PEG � poly(ethylene glycol); PLA � polylactic acid; PNIPAAM � poly(N-isopropylacrylamide); PTFE � polytetrafluoroethlyene; SDF � stromal cell–derived factor; SkM � skeletal myoblast; TGF � transforminggrowth factor; VEGF � vascular endothelial growth factor.

2619JACC

Vol.58,No.25,2011Rane

andChristm

anDecem

ber13/20,2011:2615–29Biom

aterialsfor

theTreatm

entof

MI

Cardiac Function Data From Select PublicationsTable 2 Cardiac Function Data From Select Publications

MaterialMI

Model Cells/Biological Molecules

Time Point ofTreatmentAfter MI

Time Point ofAssessment

Post-Treatment Selected Results Ref. #

LV restraints

Nitinol Sheep — Immediate 6 weeks Reduction in LV ED volume index (device: 0.20 � 0.41 vs. control:0.83 � 0.50 ml/kg) and ES volume index (device: 0.43 � 0.28 vs.control: 0.90 � 0.38 ml/kg) in treatment group compared with thecontrol.

(3)

Cardiac patch

Collagen Human Autologous bone marrow cells(250 � 106 cells)

— 10 � 3.5 months Improvement in EF at follow-up compared the baseline measurement1 week before coronary artery bypass in cell injection � cardiacpatch (25.3 � 7.3% to 32 � 5.4%) and cell injection alone (27.2 �

6.9% to 34.6 � 7.3%) groups. LV ED volume (patch: 142.4 � 24.5 mlto 112.9 � 27.3 ml, cell injection: 138.9 � 36.1 ml to 148.7 � 41ml) and scar thickness were improved in the patients that received acell-seeded collagen patch combined with cellular injection comparedwith those receiving the cell injection alone.

(11)

Collagen � Matrigel Rat Rat skeletal muscle cells(1 � 106 cells)

2 weeks 4 weeks Increased FS using a combination patch of collagen type I, Matrigel, andcells compared with baseline (patch: 33 � 5% to 42 � 6%).

(13)

Small intestinal submucosa Rabbit MSCs (1 � 106 cells) 4 weeks 4 weeks Improvement in LV ES diameter (patch � cells: 11.14 � 1.06 mm,patch: 13.12 � 1.61 mm, control: 14.98 � 1.19 mm), LV EDdiameter (patch � cells: 13.89 � 1.11 mm, patch: 15.21 � 1.46mm, control: 18.76 � 2.24 mm), and EF (patch � cells: 40.52 �

1.50%, patch: 37.34 � 2.51%, control: 30.53 � 3.58 %) with anacellular or cell-seeded patch compared with the control. Treatmentwith cell-seeded patch led to significantly greater EF compared withacellular patch.

(18)

Decellularized pericardium Rat MSCs (1.5 � 106 cells) 4 weeks 12 weeks Higher FS (patch: 37.6 � 4.7 %, control: 16.6 � 3.7%, sham 54.3 � 3.9%),and greater LV ES pressure (patch: 105.3 � 8.7 mm Hg, control:71.4 � 11.5 mm Hg, sham: 112.3 � 3.8 mm Hg) and lower LV EDpressure (patch: 6.8 � 1.7 mm Hg, control: 18.9 � 3.9 mm Hg,sham: 4.6 � 0.8 mm Hg) after treatment with MSC-layeredpericardial patch when compared with the control.

(19)

Polyester urethane urea Rat — 2 weeks 8 weeks Improvement in wall thickness, capillary density, and regional fractionalarea change in the patch-implanted group compared with the control(patch: 27 � 9.0% vs. control: 15 � 10%).

(20)

Polyurethane Rat Rat skeletal myoblasts(5 � 106 cells)

2 weeks 4 weeks Improved contractile function and EF in the cell-seeded scaffold and cellinjection alone compared with the acellular scaffold group and thecontrol (patch � cells: 48.4 � 3.1%, cells: 47.9 � 3.0%, patch:39.6 � 1.8% control: 40.1 � 4.1%).

(21,22)

Poly(glycolide-co-caprolactone) Rat Bone marrow–derivedmononuclear cells(2 � 106 cells)

1 week 4 weeks Enhanced FS (patch � cells: 32.5 � 8.6%, patch: 31.8 � 11.9%, sham:15.6 � 4.3%), LV ED diameter (patch � cells: 8.6 � 0.6 mm, patch:8.7 � 0.8 mm, sham: 11.1 � 0.5 mm), LV ES diameter (patch �

cells: 5.8 � 0.9 mm, patch: 6.0 � 1.6 mm, sham: 9.4 � 0.4 mm),and LV ED pressure (patch � cells: 2.5 � 2.3 mm Hg, patch:12.3 � 0.6 mm Hg, sham: 11.4 � 3.8 mm Hg) in scaffold alone andcell-seeded scaffold groups compared with the sham-operated group.

(24)

(Continued on next page)

2620Rane

andChristm

anJACC


aterialsfor

theTreatm

entof

MI

December13/20,2011:2615–29


MaterialMI

Model Cells/Biological Molecules




Injectable materials

Fibrin Rat Marrow-derived cardiac stem cellsalone (5 � 106 cells)

1 week 3 weeks Improved EF in all groups compared to the control (fibrin � cells: 70.77 � 2.45%, cells:55.96 � 2.56%, fibrin: 47.62 � 3.97% and control: 35.25 � 3.21 %). However greatestimprovement was seen in the cells � fibrin injected animals.

(33)

Fibrin Rat Adipose-derived stem cells(5 � 106 cells)

1 week 4 weeks Improved EF (fibrin � cells: 61.77 � 4.14%, cells: 55.75 � 3.41%, fibrin: 53.14 � 3.59%,control: 38.80 � 2.91%), LV ED diameter (fibrin � cells: 5.91 � 0.24 mm, cells:6.80 � 0.38 mm, fibrin: 6.70 � 0.41 mm, control: 7.66 � 0.30 mm), LV ES diameter(fibrin � cells: 4.24 � 0.26 mm, cells: 5.04 � 0.22 mm, fibrin: 5.24 � 0.35 mm,control: 6.50 � 0.20 mm) with injection of fibrin � cells compared with injection ofacellular fibrin or cells alone. All groups showed improvement compared with the salinecontrol.

(35)

Alginate Rat — 1 week 2 months Improved LV systolic area (alginate: 0.56 � 0.05 cm2, cells: 0.59 � 0.06 cm2, control:0.76 � 0.04 cm2) and diastolic area (alginate: 0.32 � 0.04 cm2, cells: 0.38 � 0.06 cm2,control: 0.51 � 0.04 cm2) in animals injected with alginate alone or with anintramyocardial injection of neonatal cardiomyocytes (1 � 106) compared with thesaline control.

(41)

Alginate Rat RGD, human MSCs(0.4 � 106 cells)

1 week 10 weeks Preservation of wall thickness and LV internal diameter as well as improvement in FSwith injection of RGD-modified alginate microbeads with and without human MSCscompared with baseline (alginate microbeads: 30.5 � 8.3% to 33.9 � 9.1%, cells inmicrobeads: 27.3 � 7.1% to 32.0 � 9.8%, control: 28.4 � 6.7% to 21.1% � 10.7%).

(45)

Alginate Rat RGD and YIGSR 1 week 60 days Improvement of scar thickness and FS with unmodified alginate compared to alginatemodified by RGD and YIGSR or the control RGE peptide (alginate: 34.45 � 5.4%,alginate � RGD/YIGSR: 21.63 � 3.66%, alginate � RGE: 19.59 � 3.04%, control:16.45 � 1.98%).

(46)

Alginate Pig — 3–4 days 30 days, 60 days Increased LV diastolic area compared with baseline (% change: alginate [1 ml]: 20 � 17%,alginate [2 ml]: �1 � 2%, alginate [4 ml]: �6 � 4%, control: 44 � 8%) and systolicarea (% change: alginate [1 ml]: 1.6 � 8%, alginate [2 ml]: �13 � 4%, alginate [4 ml]:�9 � 10%, control: 45 � 24%) as well as LV mass in the control animals, whereasinjection of 2 ml or 4 ml of alginate led to preservation or improvement in LV area.Injection of 2 ml of alginate increased scar thickness by 53% compared with the salinecontrol.

(29)

Small intestinal submucosa Mouse — Immediate 2 weeks, 6 weeks Improvement in LV ES area (2 weeks, SIS-B: 5.8 � 0.1 mm2, SIS-C: 7.0 � 0.4 mm2,control: 6.7 � 0.6 mm2; 6 weeks, SIS-B: 5.7 � 0.3 mm2, SIS-C: 6.9 � 0.3 mm2, control:6.7 � 0.3 mm2) and fractional area change (2 weeks, SIS-B: 34.8% � 1.1%, SIS-C:24.9 � 2.8%, control: 25.6 � 1.9%; 6 weeks, SIS-B: 31.5 � 0.8%, SIS-C: 24.7 � 1.5%,control: 24.1% � 1.9%) with SIS-B compared with SIS-C and the control at 2 weekspost-treatment, but not at 6 weeks. SIS-B–injected hearts demonstrated infarct sizereduction and increased capillary density compared with SIS-C and the control only at6 weeks after treatment.

(49)

Chitosan Rat Undifferentiated nuclear-transferredembryonic stem cells(1 � 107 cells)

1 week 4 weeks Improvement in EF (chitosan � cells: 63.6 � 4.3%, cells: 57.9 � 4.9%, chitosan: 56.8 �

2.7%, control: 33.1 � 3.0%), LV ED diameter (chitosan � cells: 7.2 � 0.3 mm, cells:7.8 � 0.3 mm, chitosan: 7.3 � 0.4 mm, control: 8.5 � 0.2 mm) and LV ES diameter(chitosan � cells: 5.1 � 0.2 mm, cells: 5.8 � 0.4 mm, chitosan: 5.9 � 0.3 mm, control:7.5 � 0.2 mm) with cells in chitosan compared with the acellular scaffold, celltransplantation alone, or saline control.

(54)

(Continued on next page)

2621JACC

Vol.58,No.25,2011Rane

andChristm

anDecem

ber13/20,2011:2615–29Biom

aterialsfor

theTreatm

entof

MI


MaterialMI

ModelCells/Biological

Molecules




Matrigel Rat — Immediate 4 weeks Increased infarct wall thickness, capillary density, and c-Kit� cells, as well as improved EF,with injection of Matrigel when compared with the saline control (Matrigel: 42.72 �

1.45%, control: 34.81 � 2.03%),

(59)

Matrigel Rat Human embryonicstem cell–derivedcardiomyocytes(10 � 106 cells) ina multicomponentpro-survival cocktail

4 days 4 weeks Improved LV ES diameter (cardiomyocytes � pro-survival cocktail: 5.8 � 0.2 mm, pro-survivalcocktail: 7.7 � 0.3 mm, media: 8.0 � 0.1 mm, noncardiac cells � pro-survival cocktail:7.3 � 0.5 mm) and EF (cardiomyocytes � pro-survival cocktail: 50.3 � 2%, pro-survivalcocktail: 45 � 1.6%, media: 42 � 1.9%, noncardiac cells � pro-survival cocktail: 43 �

4%) with injection of differentiated human embryonic stem cell–derived cardiomyocytes inthe Matrigel-containing pro-survival cocktail compared with the survival cocktail alone,media alone, or in the case of LV systolic diameter, the “noncardiac” human embryonicstem cell–derived cells.

(60)

Calcium hydroxyapatite Sheep — 3 h 8 weeks Enhancement of EF (calcium hydroxyapatite: 31.3 � 2.6%, control: 27.6 � 1.3%), LV ESvolume (calcium hydroxyapatite: 60.8 � 4.3 ml, control: 80.3 � 6.9 ml), LV ED volume(calcium hydroxyapatite: 87.2 � 4.0 ml, control: 110.6 � 8.4 ml), as well as a decrease ininfarct expansion and longitudinal strain, after calcium hydroxyapatite treatmentcompared with the control.

(61)

Calcium hydroxyapatite Sheep — 45 min 4 weeks Improvement in EF (calcium hydroxyapatite: 37.3 � 1.7%, control: 29.5 � 1.6%) and LV ESvolume (calcium hydroxyapatite: 44.5 � 3.9 ml, control: 61.2 � 3.6 ml) with calciumhydroxyapatite compared with the control.

(62)

Poly(N-isopropylacrylamide-co-propylacrylic acid-co-butyl acrylate)(p[NIPAAm-co-PAA-co-BA])

Rat bFGF Immediate 4 weeks Increase in vessel density (30% to 40%) and FS in the hydrogel � bFGF group compared tothe hydrogel alone and bFGF control (hydrogel � bFGF: 30 � 1.4%, hydrogel: 25 � 1.2%,control: 25 � 1.8%).

(69)

PEG Rat EPO Immediate 30 days Improvement in FS (PEG � EPO: 26.93 � 2.49%, PEG: 22.53 � 3.21%, EPO: 21.98 �

3.04%, control: 19.57 � 4.20%), LV ED diameter (PEG � EPO: 7.4 � 0.4 mm, PEG:8.51 � 0.70 mm, EPO: 8.85 � 0.72 mm, control: 10.33 � 0.78 mm) and LV ES diameter(PEG � EPO: 5.48 � 0.51 mm, PEG: 6.61 � 0.80 mm, EPO: 6.85 � 0.58 mm, control:8.22 � 1.01 mm) with injection of the PEG � EPO gel compared with the polymer aloneand EPO alone. However, all groups demonstrated improvement compared with the salinecontrol.

(70)

PEG Rat — Immediate 4 weeks,13 weeks

Increase in wall thickness and reduction in LV ED diameter with PEG compared with thesaline control at 4 weeks, but effect was diminished by 13 weeks (4 weeks, PEG:8.5 � 0.2 mm, control: 9.2 � 0.2 mm, 13 weeks, PEG: 10.2 � 0.3 mm, control:10.2 � 0.3 mm).

(74)

PEG Rat — 1 week 6 weeks Increase in wall thickness with PEG; however, a decrease in EF (PEG: 44.20 � 8.52%, control:42.96 � 6.58%), as well as an increase in LV ED volume (PEG: 487.1 � 109.9 mm3, control:502.6 � 131.1 mm3) and LV ES volume (PEG: 282.6 � 104.2 mm3, control:288.8 � 102.3 mm3), in both PEG- and saline-injected animals.

(75)

Hyaluronic acid and PEG Rat — 2 weeks 4 weeks Improvement in EF (hyaluronic acid: 42.74 � 7.53%, control: 18.17 � 5.42%, sham: 48.50� 8.02%) and elastance in hyaluronic acid � PEG group compared towith the control.

(77)

Peptide nanofibers Mini pigs Bone marrowmononuclear cells(1 � 108 cells)

Immediate 1 month Improvement in LV ES volume (nanofiber � cells: 51.7 � 4.6 ml, cells: 58.7 � 2.4 ml,nanofibers: 73.7 � 3.6 ml, control: 103.0 � 7.0 ml), and LV ED volume (nanofiber � cells:113.6 � 6.1 ml, cells: 115.0 � 5.7 ml, nanofibers: 120.3 � 7.0 ml, control: 147.5 � 7.0 ml) inall groups compared with the control.

(80)

bFGF � basic fibroblast growth factor; ED � end diastolic; EF � ejection fraction; EPO � erythropoietin; ES � end systolic; FS � fractional shortening; LV � left ventricle; MI � myocardial infarction; MSC � mesenchymal stem cell; PEG � poly(ethylene glycol).

2622Rane

andChristm

anJACC


aterialsfor

theTreatm

entof

MI

December13/20,2011:2615–29


myofibroblasts. In addition, alginate was injected in lateinfarcts (8 weeks) and assessed 2 months later, showing asimilar increase in scar thickness and improvement insystolic and diastolic function. Delivery of vascular endo-thelial growth factor (VEGF) as well as sequential deliveryof VEGF followed by platelet-derived growth factor (42) orinsulin-like growth factor and hepatocyte growth factor (43)in alginate showed improvement in LV remodeling com-pared with the biomaterial alone and the control 4 weekspost-injection in a rat MI. The effects of surface modifica-tion of alginate was also studied by injection of alginatemodified with RGD or unmodified alginate 5 weekspost-MI into a rat LV aneurysm model. Improvement inLV ES and ED diameter as well increased arteriole presencewas observed in both groups compared with saline (44).Injection of RGD-modified alginate microbeads with andwithout human MSCs in a 1-week rodent MI led toimprovement in FS and preservation of wall thickness andLV internal diameter 10 weeks post-injection (45). Con-trary to these studies, Tsur-Gang et al. (46) showed thatmodification of alginate by RGD and YIGSR or the controlRGE peptide was not as effective as unmodified alginate inimprovement of scar thickness and FS, 60 days post-injection into a 1-week rat infarct. It is hypothesized that thisdiscrepancy could be due to alteration in viscosity uponaddition of the peptides that led to changes in distribution ofthe material and reduced coverage of the infarct. In addition,alginate has been blended with the electroactive polymerpolypyrrole showing an increase in arteriole density 5 weekspost-treatment compared with alginate alone and saline upon

Figure 2 Clinical Case From the MAGNUM Trial

A human heart treated with a bone marrow cell–seeded collagen matrix patchafter coronary artery bypass graft and cell injection. Reprinted, with permission,from Chachques et al. (11).

injection in a rat MI (47). Leor et al. (29) carried out

pre-clinical work with alginate in a swine MI model showingthat intracoronary injection of alginate led to prevention andreversal of negative LV remodeling. Saline-injected animalshad an increase in LV ED and ES area as well as LV mass,however injection of 2 ml or 4 ml of alginate led topreservation or improvement in LV area, but not FS. The2-ml injection increased scar thickness by 53% comparedwith saline, possibly due to myofibroblast migration anddeposition of collagen (Fig. 3) (29). These results haverecently led to a first-in-man safety and feasibility study ofintracoronary injection of alginate in acute MI patients (26).

As with cardiac patches, the use of decellularization as atechnique for preparation of injectable materials is growingat a rapid pace. Injection of decellularized SIS extracellularmatrix into an ischemia-reperfusion rat model promoted cellmigration (c-kit� cells, myofibroblasts, and macrophages)and improvement in cardiac function in terms of EF andstroke volume compared with the saline control (48). Okada etal. (49) injected 2 forms of SIS-derived gels immediatelypost-MI in a murine model. One form, SIS-B, improved LVES area and fractional area change compared with SIS-C andthe control at 2 weeks post-treatment, but not at 6 weeks.However, SIS-B reduced infarct size and increased capillarydensity compared with SIS-C and the control, only at 6 weeks.These differences are potentially attributed to increased bFGFcontent and greater stiffness of the gel. Although generalextracellular matrix components among tissues are similar,heterogeneity exists in the combination of proteins and pro-teoglycans (50). Given the complex extracellular structure ofthe heart, the injection of a cardiac-specific matrix may bebetter suited for treating the myocardium. Singelyn et al. (51)developed an injectable hydrogel form of decellularized porcineventricular tissue, which was first tested in healthy myocar-dium. More recently, it was shown that this material preservedcardiac function in a rat MI model and is compatible withpercutaneous transendocardial delivery in pigs (28). Seif-Naraghi et al. created and injected an acellular pericardialmatrix gel into healthy rodent myocardium as proof-of-concept for a potentially autologous therapy for MI (52) andhas also demonstrated that this material can be formed fromsamples from a variety of human patients (53). The pericardialmatrix induced neovascularization and the recruitment c-kit�

cells (52).A few other bio-derived materials have been examined for

treating MI. Chitosan, a naturally occurring polysaccharidederived from crustacean shells, was injected with undiffer-entiated embryonic stem cells 1 week post-MI, resulting inimprovement in EF and LV ED and ES diameters com-pared with the acellular scaffold, cell transplantation alone,or saline in a rodent MI model 4 weeks post-injection(54,55). The co-injection of a chitosan with bFGF im-proved EF, FS, LV diameters, and arteriole density, as wellas decreased infarct size and fibrotic area compared with theinjection of bFGF alone 4 weeks post-transplantation in arodent MI (56). Similarly, gelatin with bFGF has shown
improvements in cardiac function in both small (57) and


large (58) animals. Injection of Matrigel alone immediatelypost-infarction led to increased infarct wall thickness, im-proved EF, as well as increased capillary density and c-Kit�

cells, when compared with saline in a rat MI model, 4 weekspost-injection (59). Laflamme et al. (60) injected humanembryonic stem cell–derived cardiomyocytes in a multicom-ponent pro-survival cocktail containing Matrigel in a ratocclusion-reperfusion model 4 days post-MI. After 4 weeks,the pro-survival factors resulted in significantly increasedcell survival. In addition, injection of this combination led toattenuation of LV remodeling post-MI as demonstrated byreduced ventricular dilation, improved global cardiac func-tion, and increased wall motion. In addition, delivery ofacellular calcium hydroxyapatite into an ovine MI model ledto improvement in EF and LV volume compared with thecontrol 4 weeks and 8 weeks post-MI as well as a decreasein infarct expansion and longitudinal stain (61,62).

In the past 5 years, synthetic injectable polymers havebegun to be examined as a treatment for MI. In contrast tobiologically derived materials, synthetic materials allow forcontrol over properties such as degradation, stiffness, poros-ity, and gelation time, and do not suffer from the batch-to-batch variability that occurs with bio-derived materials. Amatrix metalloproteinase–degradable poly(ethylene glycol)(PEG) loaded with thymosin �-4 and endothelial (0.66 �106 cells) and smooth muscle-like (0.33 � 106 cells) cellsderived from human embryonic stem cells improved EF andED and ES volumes, as well as decreased infarct size andincreased vessel density, compared with the control (63). A

Figure 3 Intracoronary Alginate Injection

Brown staining indicates alginate gelled inside porcine myocardium. Reprinted, wit

similar result was seen with injection of degradable poly(N-

isopropylacrylamide)-based (64–66) and PEG-based (67,68)gels with or without cells in a MI. Garbern et al. (69)injected a pH- and temperature-responsive hydrogel loadedwith bFGF immediately post-MI in a rat and showed a 30%to 40% increase in vessel density as well as an increase in FScompared with the hydrogel alone and bFGF injected insaline 28 days post-treatment. Similarly, delivery of eryth-ropoietin with a PEG-based gel into a rat immediatelypost-MI led to an improvement in FS and LV ED and ESdiameters compared with injection of polymer alone anderythropoietin alone; however, all groups demonstratedimprovement compared with saline, 30 days post-MI (70).Along the same lines, VEGF was either mixed or conju-gated to a hydrogel for delivery into a rat 1 week post-MI.At 35 days post-injection, EF, ED and ES volumes, scarthickness, and vessel density were improved in the group inwhich the VEGF was tethered to the hydrogel whencompared with the animals injected with unconjugatedVEGF, hydrogel alone, and saline (71), thus indicating thattethering growth factors to biomaterials can lead to greaterbeneficial effects. Poly(NIPAAM-co-acrylic acid) hydrogelswith matrix metalloproteinase degradable crosslinkers wereused to transplant bone marrow–derived mononuclear cells(2 � 105 cells) into infarcted mouse myocardium. However,injection of the material alone led to the greatest improve-ment in EF (72). In the past, Wall et al. (73) usedcomputational modeling to suggest that the presence of amaterial alone at the site of infarction may lead to animprovement in cardiac function due to an increase in wall

ission, from Leor et al. (29).
h perm
thickness leading to a subsequent decrease in wall stress due

pFa(inrefaa

F

Opmdf

mtcci

mbpsfatinfeusvdsmchtossSacdeia

umImbhficpHlpiale


to Laplace’s Law. In order to study the effect of a nonde-gradable material on pathological remodeling, Dobner et al.(74) injected a nondegradable PEG hydrogel immediatelypost-MI in a rat model. Although LV ED diameter wasreduced and wall thickness was increased at 4 weeks, by 13weeks, pathological progression was similar to that ofsaline-injected animals. Similarly, Rane et al. (75) showedthat even after injection at the clinically relevant time pointof 1 week post-MI in a rat, increase in wall thickness aloneby injection of a bio-inert PEG was insufficient to preventthe downward spiral of LV remodeling. PEG-injectedanimals showed a decline in EF and LV ED and ESvolumes similar to that of saline, 7 weeks post-MI. Theseresults suggest that inherent bioactivity and/or materialdegradation allowing for cell infiltration may be the mech-anisms by which injectable materials affect cardiac function.Material properties of injectable biomaterials have recentlycome under investigation; Ifkovits et al. (76) examined theeffect of material stiffness on cardiac function and LVremodeling in an ovine MI model. Methacrylated hyal-uronic acid was tailored to a stiffness of 8 kPa and 43 kPa,and injected into the infarct 30 min post-MI. Althoughthere were no significant differences in functional parame-ters, infarct area was reduced in the group injected with astiffer hydrogel at 8 weeks (76). Another study injected a gelcomprised of hyaluronic acid and PEG in a 2-week rodentMI and showed a clear improvement in EF and elastancecompared with the control animals 4 weeks post-treatment(77). However, the stiffness of the gel was not measured, soit is difficult to compare the results of this study with thoseof Ifkovits et al. (76).

Bio-inspired self-assembling peptide nanofibers havebeen used as a platform for cell and growth factor delivery inboth small (78,79) and (80) large animals. Davis et al. (78)demonstrated that tethering insulin-like growth factor-1 topeptide nanofibers along with neonatal cardiomyocytes (5 �105 cells) improved systolic function in a rat MI 21 days

ost-infarction compared with untethered growth factor.ollowing this study, Lin et al. (80) injected mini pigs withutologous bone marrow mononuclear cells, peptide nanofibers1% in saline), or a combination of both at the site of infarctionmmediately post-MI (Fig. 4). Injection of cells with theanofibers improved both diastolic and systolic function. Mostecently, self-assembling peptides were utilized for dual deliv-ry of platelet-derived growth factor and fibroblast growthactor 2 into a rat infarct, showing reduction in infarct size inddition to an increase in capillary and arteriole density at 4nd 8 weeks post-MI (81).

uture Directions

ver the last 5 years, there has been a rapid increase in newublications in the field of cardiac biomaterials. Althoughany investigated materials remained the same over the last

ecade, in recent years, new materials have been developed
or myocardial tissue engineering, most notably synthetic a
aterials and decellularized extracellular matrices. Many ofhe materials initially studied continue to be investigated inonjunction with different cell types and biological mole-ules. Remarkably, most studies have led to an improvementn cardiac function and neovascularization.

One concern, however, is the contradictory results seen inany cardiac patch studies. Piao et al. (24) showed that

one marrow mononuclear cells seeded on a degradableoly-glycolide-co-caprolactone scaffold and the acellularcaffold reduced LV dilation and preserved LV systolicunction. Similar results were seen after applying a degrad-ble polyester urethane urea cardiac patch (20). Contrary tohe aforementioned results, Jin et al. (25) showed thatmplantation of polylactide-co-�-caprolactone alone wasot able to improve EF or decrease infarct size. The reasonor this is not clear, but could be attributed to differences inxperimental conditions. Further studies are needed tonderstand the efficacy of acellular patches versus cell-eeded implants and the benefits and drawbacks of syntheticersus bio-derived scaffolds. In the case of a syntheticegradable scaffold, the scaffold functions as a temporaryupport for the cells before they integrate into the hostyocardium. The material properties of synthetic materials

an be modulated to attain elastic properties suitable for theeart’s dynamic environment and may also temporarily alterhe mechanical environment and reduce wall stress. On thether hand, a biologically active scaffold can provide auitable microenvironment in addition to serving as aupport. For instance, Tan et al. (18) demonstrated that anIS graft seeded with MSCs was more effective than the SIS graftlone, though both patches were able to improve LVontractile function, dimension, and capillary density. Aeeper fundamental understanding of the mechanisms gov-rning the improvement in cardiac function seen with patchmplantation may allow for further insight into the materialsnd/or cells best suited for this therapy.

In the last 2 years, there has been an emphasis onnderstanding the mechanisms responsible for improve-ent in cardiac function seen with injectable biomaterials.

fkovits et al. (76) studied the effect of changing materialechanics, showing injection of stiffer materials to be

eneficial for reducing infarct size, whereas other studiesave assessed the impact of structural reinforcement on LVunction (74,75). Until recently, it was thought that anncrease in wall thickness alone by injectable materials orardiac patches can lead to a decrease in wall stress,reventing infarct expansion and negative LV remodeling.owever, studies have shown that this is not sufficient for

ong-term improvement in function (69,74,75). This couldossibly be due to nonuniformity in polymer spread allow-ng for regional and global abnormalities in function, as wells infarct expansion in areas where the polymer has notocalized. Further studies are needed to fully understand theffects of polymer spread and stiffness on infarct expansion
nd deterioration of cardiac function.


Ventricular twist and torsion are thought to play animportant role in cardiac pump function. Ventricular twist isconserved among species, making it an important parameterto extrapolate data among small animals, large animals, andhumans (82). To date, limited studies (61,83,84) haveinvestigated the effect of biomaterial therapies on importantclinical parameters such as cardiac strain, twist, and torsion.Additionally, very few groups have studied the electricalintegration of cells that have been implanted in or migrateinto a scaffold (14). As seen with the transplantation of cells

Figure 4 Injection of Peptide NFs With Autologous MNCs in Po

MI � myocardial infarction; MNC � bone marrow mononuclear cell; NF � nanofibe

(85), arrhythmia vulnerability due to injectable materials

and cardiac patches is a valid and understudied concern. Inthe MAGNUM phase I clinical trial, there was no increasein proarrhythmic events or incidence of ventricular tachy-cardia post-implantation of a collagen scaffold with bonemarrow cells (11). However, this study was performed on asmall cohort of patients, so the issue of arrhythmogenicityneeds to be further investigated for all biomaterial MItherapies prior to human translation.

Most of the biomaterials that have been examined aredegradable, with the degradation rate ranging from 1 to 6

MI Model

� saline. Reprinted, with permission, from Lin et al. (80).

rcine

rs; NS

weeks for most injectable biomaterials. After MI, collagen


type I decreases from 80% to 40%, thus creating a need forstructural reinforcement (86). Although biomaterials mayfunction as a structural support at early time points toprevent wall thinning, the timely degradation of thesepolymers may allow for cellular infiltration. These cells maybe advantageous for changing the infarct milieu by increas-ing neovascularization, modulating the inflammatory re-sponse, and/or generating other positive paracrine factors.

An exciting development over the last 5 years is thebeginning of clinical translation of cardiac patches andinjectable materials. The safety and feasibility of collagencardiac patches was demonstrated in the MAGNUM phaseI clinical trial (11). As with LV restraint devices, onedrawback of cardiac patches is the invasive procedurerequired for these approaches. In contrast, some injectablematerials can be injected minimally invasively using catheterdelivery (27). Alginate has been delivered in a small phase I/IIstudy in acute MI patients (26), and will be further examinedin the phase II PRESERVATION I (IK-500 for the Preven-tion of Remodeling of the Ventricle and Congestive HeartFailure After Acute Myocardial Infarction) trial. The myocar-dial matrix hydrogel has also been delivered via catheter andshown to improve EF in a porcine MI model (data unpub-lished), demonstrating its potential clinical translatability.

However, there are significant obstacles to be overcomebefore widespread application to patients is possible. Asmentioned in the original review (2), long-term studies areneeded to better understand the efficacy of these approaches.For example, Dobner et al. (74) showed that injection of apolymer can improve cardiac function at early time points,but at later time points, that effect is lost. In addition, asuitable human cell source still needs to be identified forcell-based therapies. Although large-scale regeneration willlikely require an exogenous cell source, to date, many studieshave shown improvements with a biomaterial alone, suggestingthe cells that are currently injected may not provide additionalbenefit if the appropriate material scaffold is employed. Lastly,it is critical to keep clinical translation in mind when designingnew biomaterial therapies. For example, numerous injectablebiomaterials have been developed, yet only a few can truly bedelivered via a catheter-based approach.

Conclusions

Biomaterials for the treatment of MI continues to be apromising approach. Though interest in LV restraints iswaning, much progress has been made in cardiac patchesand injectable biomaterials, with these therapies recentlyentering clinical trials. As these materials move towardsclinical translation, it is becoming increasingly importantthat we understand the mechanisms by which these thera-pies affect cardiac function, LV remodeling, and cardiac
electrophysiology.
Reprint requests and correspondence: Dr. Karen L. Christman,Department of Bioengineering, University of California, SanDiego, 9500 Gilman Drive, MC 0412, La Jolla, California 92093.E-mail: [email protected].

REFERENCES

1. Sutton MG, Sharpe N. Left ventricular remodeling after myocardialinfarction: pathophysiology and therapy. Circulation 2000;101:2981–8.

2. Christman KL, Lee RJ. Biomaterials for the treatment of myocardialinfarction. J Am Coll Cardiol 2006;48:907–13.

3. Magovern JA, Teekell-Taylor L, Mankad S, et al. Effect of a flexibleventricular restraint device on cardiac remodeling after acute myocar-dial infarction. ASAIO J 2006;52:196–200.

4. George I, Cheng Y, Yi GH, et al. Effect of passive cardiac contain-ment on ventricular synchrony and cardiac function in awake dogs. EurJ Cardiothorac Surg 2007;31:55–64.

5. Klodell CT Jr., Aranda JM Jr., McGiffin DC, et al. Worldwidesurgical experience with the Paracor HeartNet cardiac restraint device.J Thorac Cardiovasc Surg 2008;135:188–95.

6. Sarig U, Machluf M. Engineering cell platforms for myocardialregeneration. Expert Opin Biol Ther 2011;11:1055–77.

7. Callegari A, Bollini S, Iop L, et al. Neovascularization induced byporous collagen scaffold implanted on intact and cryoinjured rat hearts.Biomaterials 2007;28:5449–61.

8. Pozzobon M, Bollini S, Iop L, et al. Human bone marrow-derivedCD133(�) cells delivered to a collagen patch on cryoinjured rat heartpromote angiogenesis and arteriogenesis. Cell transplantation 2010;19:1247–60.

9. Simpson D, Liu H, Fan TM, Nerem R, Dudley SC. A tissueengineering approach to progenitor cell delivery results in significantcell engraftment and improved myocardial remodeling. Stem Cells2007;25:2350–7.

10. Hamdi H, Furuta A, Bellamy V, et al. Cell delivery: intramyocardialinjections or epicardial deposition? A head-to-head comparison. AnnThorac Surg 2009;87:1196–203.

11. Chachques JC, Trainini JC, Lago N, Cortes-Morichetti M, SchusslerO, Carpentier A. Myocardial Assistance by Grafting a New Bioarti-ficial Upgraded Myocardium (MAGNUM trial): clinical feasibilitystudy. Ann Thorac Surg 2008;85:901–8.

12. Cortes-Morichetti M, Frati G, Schussler O, et al. Association betweena cell-seeded collagen matrix and cellular cardiomyoplasty for myocar-dial support and regeneration. Tissue Eng 2007;13:2681–7.

13. Giraud MN, Ayuni E, Cook S, Siepe M, Carrel TP, Tevaearai HT.Hydrogel-based engineered skeletal muscle grafts normalize heart func-tion early after myocardial infarction. Artif Organs 2008;32:692–700.

14. Dvir T, Kedem A, Ruvinov E, et al. Prevascularization of cardiac patchon the omentum improves its therapeutic outcome. Proc Natl Acad SciU S A 2009;106:14990–5.

15. Xiong Q, Hill KL, Li Q, et al. A fibrin patch-based enhanced deliveryof human embryonic stem cell-derived vascular cell transplantation ina porcine model of postinfarction left ventricular remodeling. StemCells 2011;29:367–75.

16. Ott HC, Matthiesen TS, Goh SK, et al. Perfusion-decellularizedmatrix: using nature’s platform to engineer a bioartificial heart. NatMed 2008;14:213–21.

17. Godier-Furnémont AF, Martens TP, Koeckert MS, et al. Compositescaffold provides a cell delivery platform for cardiovascular repair. ProcNatl Acad Sci U S A 2011;108:7974–9.

18. Tan MY, Zhi W, Wei RQ, et al. Repair of infarcted myocardiumusing mesenchymal stem cell seeded small intestinal submucosa inrabbits. Biomaterials 2009;30:3234–40.

19. Wei H, Chen C, Lee W, et al. Bioengineered cardiac patch con-structed from multilayered mesenchymal stem cells for myocardialrepair. Biomaterials 2008;29:3547–56.

20. Fujimoto KL, Tobita K, Merryman WD, et al. An elastic, biodegrad-able cardiac patch induces contractile smooth muscle and improvescardiac remodeling and function in subacute myocardial infarction.
J Am Coll Cardiol, 2007;49:2292–300.
mailto:[email protected]

3

4

4

4

4

4

4

4

4

4

4

5

5

5

5

5

5

5

5

5

5

6

6

6

6


21. Siepe M, Giraud MN, Pavlovic M, et al. Myoblast-seeded biodegrad-able scaffolds to prevent post-myocardial infarction evolution towardheart failure. J Thorac Cardiovasc Surg 2006;132:124–31.

22. Siepe M, Giraud M, Liljensten E, et al. Construction of skeletalmyoblast-based polyurethane scaffolds for myocardial repair. ArtifOrgans 2007;31:425–33.

23. Giraud MN, Flueckiger R, Cook S, et al. Long-term evaluation ofmyoblast seeded patches implanted on infarcted rat hearts. ArtifOrgans 2010;34:E184–92.

24. Piao H, Kwon J, Piao S, et al. Effects of cardiac patches engineeredwith bone marrow-derived mononuclear cells and PGCL scaffolds ina rat myocardial infarction model. Biomaterials 2007;28:641–9.

25. Jin J, Jeong SI, Shin YM, et al. Transplantation of mesenchymal stemcells within a poly(lactide-co-epsilon-caprolactone) scaffold improvescardiac function in a rat myocardial infarction model. Eur J Heart Fail2009;11:147–53.

26. BioLineRx L. Safety and Feasibility of the Injectable BL-1040Implant. Study NCT00557531, 2009. Available at: http://www.ClinicalTrials.gov. Accessed August 1, 2011.

27. Singelyn JM, Christman KL. Injectable materials for the treatment ofmyocardial infarction and heart failure: the promise of decellularizedmatrices. J Cardiovasc Transl Res 2010;3:478–86.

28. Singelyn JM, Sundaramurthy P, Johnson TD, et al. Catheter-deliverable hydrogel derived from decellularized ventricular extracellu-lar matrix increases endogenous myocytes and preserves cardiac func-tion post-myocardial infarction. J Am Coll Cardiol 2011. In press.

29. Leor J, Tuvia S, Guetta V, et al. Intracoronary injection of in situforming alginate hydrogel reverses left ventricular remodeling aftermyocardial infarction in Swine. J Am Coll Cardiol 2009;54:1014–23.

30. Christman KL, Fok HH, Sievers RE, Fang Q, Lee RJ. Fibrin gluealone and skeletal myoblasts in a fibrin scaffold preserve cardiacfunction after myocardial infarction. Tissue Eng 2004;10:403–9.

31. Christman KL, Vardanian AJ, Fang Q, Sievers RE, Fok HH, Lee RJ.Injectable fibrin scaffold improves cell transplant survival, reducesinfarct expansion, and induces neovasculature formation in ischemicmyocardium. J Am Coll Cardiol 2004;44:654–60.

32. Nakamuta JS, Danoviz ME, Marques FLN, et al. Cell therapy attenuatescardiac dysfunction post myocardial infarction: effect of timing, routes ofinjection and a fibrin scaffold. PLoS ONE 2009;4:e6005.

33. Guo HD, Wang HJ, Tan YZ, Wu JH. Transplantation of marrow-derived cardiac stem cells carried in fibrin improves cardiac functionafter myocardial infarction. Tissue Eng Pt A 2011;17:45–58.

34. Danoviz ME, Nakamuta JS, Marques FLN, et al. Rat adiposetissue-derived stem cells transplantation attenuates cardiac dysfunctionpost infarction and biopolymers enhance cell retention. PLoS ONE2010;5:e12077.

35. Zhang X, Wang H, Ma X, et al. Preservation of the cardiac functionin infarcted rat hearts by the transplantation of adipose-derived stemcells with injectable fibrin scaffolds. Exp Biol Med (Maywood)2010;235:1505–15.

36. Nie SP, Wang X, Qiao SB, et al. Improved myocardial perfusion andcardiac function by controlled-release basic fibroblast growth factorusing fibrin glue in a canine infarct model. J Zhejiang Univ Sci B2010;11:895–904.

37. Zhang G, Hu Q, Braunlin EA, Suggs LJ, Zhang J. Enhancing efficacyof stem cell transplantation to the heart with a PEGylated fibrinbiomatrix. Tissue Eng Pt A 2008;14:1025–36.

38. Yang HS, Bhang SH, Kim IK, et al. In situ cardiomyogenic differ-entiation of implanted bone marrow mononuclear cells by localdelivery of transforming growth factor-�1. Cell Transplant 2011 Jun 7[E-pub ahead of print].

9. Mukherjee R, Zavadzkas JA, Saunders SM, et al. Targeted myocardialmicroinjections of a biocomposite material reduces infarct expansion inpigs. Ann Thorac Surg 2008;86:1268–77.

0. Leor J, Amsalem Y, Cohen S. Cells, scaffolds, and molecules formyocardial tissue engineering. Pharmacol Ther 2005;105:151–63.

1. Landa N, Miller L, Feinberg MS, et al. Effect of injectable alginateimplant on cardiac remodeling and function after recent and oldinfarcts in rat. Circulation 2008;117:1388–96.

2. Hao X, Silva EA, Månsson-Broberg A, et al. Angiogenic effects ofsequential release of VEGF-A165 and PDGF-BB with alginate hydro-gels after myocardial infarction. Cardiovasc Res 2007;75:178–85.

3. Ruvinov E, Leor J, Cohen S. The promotion of myocardial repair by
the sequential delivery of IGF-1 and HGF from an injectable alginate
biomaterial in a model of acute myocardial infarction. Biomaterials2011;32:565–78.

4. Yu J, Gu Y, Du KT, Mihardja S, Sievers RE, Lee RJ. The effect ofinjected RGD modified alginate on angiogenesis and left ventricularfunction in a chronic rat infarct model. Biomaterials 2009;30:751–6.

5. Yu J, Du KT, Fang Q, et al. The use of human mesenchymal stem cellsencapsulated in RGD modified alginate microspheres in the repair ofmyocardial infarction in the rat. Biomaterials 2010;27:7012–20.

6. Tsur-Gang O, Ruvinov E, Landa N, et al. The effects of peptide-basedmodification of alginate on left ventricular remodeling and functionafter myocardial infarction. Biomaterials 2009;30:189–95.

7. Mihardja SS, Sievers RE, Lee RJ. The effect of polypyrrole onarteriogenesis in an acute rat infarct model. Biomaterials 2008;29:4205–10.

8. Zhao ZQ, Puskas JD, Xu D, et al. Improvement in cardiac functionwith small intestine extracellular matrix is associated with recruitmentof C-kit cells, myofibroblasts, and macrophages after myocardialinfarction. J Am Coll Cardiol 2010;55:1250–61.

9. Okada M, Payne TR, Oshima H, Momoi N, Tobita K, Huard J.Differential efficacy of gels derived from small intestinal submucosa asan injectable biomaterial for myocardial infarct repair. Biomaterials2010;31:7678–83.

0. Lutolf MP, Hubbell JA. Synthetic biomaterials as instructive extracel-lular microenvironments for morphogenesis in tissue engineering. NatBiotechnol 2005;23:47–55.

1. Singelyn JM, DeQuach JA, Seif-Naraghi SB, Littlefield RB, Schup-Magoffin PJ, Christman KL. Naturally derived myocardial matrix as aninjectable scaffold for cardiac tissue engineering. Biomaterials 2009;30:5409–16.

2. Seif-Naraghi SB, Salvatore MA, Schup-Magoffin PJ, Hu DP, Christ-man KL. Design and characterization of an injectable pericardialmatrix gel: a potentially autologous scaffold for cardiac tissue engineer-ing. Tissue Eng Pt A 2010;16:2017–2027.

3. Seif-Naraghi SB, Horn D, Schup-Magoffin PA, Madani MM,Christman KL. Patient-to-patient variability in autologous pericardialmatrix scaffolds for cardiac repair. J Cardiovasc Transl Res 2011;4:545–56.

4. Lue S, Wang H, Lu W, et al. Both the transplantation of somatic cellnuclear transfer- and fertilization-derived mouse embryonic stem cellswith temperature-responsive chitosan hydrogel improve myocardial per-formance in infarcted rat hearts. Tissue Eng Pt A 2010;16:1303–15.

5. Lu WN, Lü SH, Wang HB, et al. Functional improvement ofinfarcted heart by co-injection of embryonic stem cells withtemperature-responsive chitosan hydrogel. Tissue Eng Pt A 2009;15:1437–47.

6. Wang H, Zhang X, Li Y, et al. Improved myocardial performance ininfarcted rat heart by co-injection of basic fibroblast growth factor withtemperature-responsive Chitosan hydrogel. J Heart Lung Transpl2010;29:881–7.

7. Shao ZQ, Takaji K, Katayama Y, et al. Effects of intramyocardialadministration of slow-release basic fibroblast growth factor on angio-genesis and ventricular remodeling in a rat infarct model. Circ J2006;70:471–7.

8. Liu Y, Sun L, Huan Y, Zhao H, Deng J. Effects of basic fibroblastgrowth factor microspheres on angiogenesis in ischemic myocardiumand cardiac function: analysis with dobutamine cardiovascular mag-netic resonance tagging. Eur J Cardio-Thorac 2006;30:103–7.

9. Ou L, Li W, Zhang Y, et al. Intracardiac injection of matrigel inducesstem cell recruitment and improves cardiac functions in a rat myocar-dial infarction model. J Cell Mol Med 2011;15:1310–8.

0. Laflamme MA, Chen KY, Naumova AV, et al. Cardiomyocytesderived from human embryonic stem cells in pro-survival factorsenhance function of infarcted rat hearts. Nat Biotechnol 2007;25:1015–24.

1. Morita M, Eckert CE, Matsuzaki K, et al. Modification of infarctmaterial properties limits adverse ventricular remodeling. Ann ThoracSurg 2011;92:617–24.

2. Ryan LP, Matsuzaki K, Noma M, et al. Dermal filler injection: a novelapproach for limiting infarct expansion. Ann Thorac Surg 2009;87:148–55.

3. Kraehenbuehl TP, Ferreira LS, Hayward AM, et al. Human embry-onic stem cell-derived microvascular grafts for cardiac tissue preserva-
tion after myocardial infarction. Biomaterials 2011;32:1102–9.
http://www.ClinicalTrials.gov

http://www.ClinicalTrials.gov

7

7

7

8

8

8

8

8

8

8


64. Fujimoto KL, Ma Z, Nelson DM, et al. Synthesis, characterizationand therapeutic efficacy of a biodegradable, thermoresponsive hydrogeldesigned for application in chronic infarcted myocardium. Biomateri-als 2009;30:4357–68.

65. Li XY, Wang T, Jiang XJ, et al. Injectable hydrogel helps bonemarrow-derived mononuclear cells restore infarcted myocardium. Car-diology 2010;115:194–9.

66. Wang T, Wu DQ, Jiang XJ, et al. Novel thermosensitive hydrogelinjection inhibits post-infarct ventricle remodelling. Eur J Heart Fail2009;11:14–9.

67. Jiang XJ, Wang T, Li XY, et al. Injection of a novel synthetic hydrogelpreserves left ventricle function after myocardial infarction. J BiomedMater Res A 2009;90:472–7.

68. Wang T, Jiang XJ, Tang Q, et al. Bone marrow stem cells implanta-tion with alpha-cyclodextrin/MPEG-PCL-MPEG hydrogel improvescardiac function after myocardial infarction. Acta Biomater 2009;5:2939–44.

69. Garbern JC, Minami E, Stayton PS, Murry CE. Delivery of basicfibroblast growth factor with a pH-responsive, injectable hydrogel toimprove angiogenesis in infarcted myocardium. Biomaterials 2011;32:2407–16.

70. Wang T, Jiang XJ, Lin T, et al. The inhibition of postinfarct ventricleremodeling without polycythaemia following local sustained intramyo-cardial delivery of erythropoietin within a supramolecular hydrogel.Biomaterials 2009;30:4161–7.

71. Wu J, Zeng F, Huang X, et al. Infarct stabilization and cardiac repairwith a VEGF-conjugated, injectable hydrogel. Biomaterials 2011;32:579–86.

72. Wall ST, Yeh CC, Tu RY, Mann MJ, Healy KE. Biomimeticmatrices for myocardial stabilization and stem cell transplantation.J Biomed Mater Res A 2010;95:1055–66.

73. Wall ST, Walker JC, Healy KE, Ratcliffe MB, Guccione JM.Theoretical impact of the injection of material into the myocardium: afinite element model simulation. Circulation 2006;114:2627–35.

74. Dobner S, Bezuidenhout D, Govender P, Zilla P, Davies N. Asynthetic non-degradable polyethylene glycol hydrogel retards adversepost-infarct left ventricular remodeling. J Card Fail 2009;15:629–36.

75. Rane AA, Chuang JS, Shah A, et al. Increased infarct wall thicknessby a bio-inert material is insufficient to prevent negative left ventricularremodeling after myocardial infarction. PLoS ONE 2011;6:e21571.

76. Ifkovits JL, Tous E, Minakawa M, et al. Injectable hydrogel propertiesinfluence infarct expansion and extent of postinfarction left ventricular

remodeling in an ovine model. Proc Natl Acad Sci U S A 2010;107:11507–12.

7. Yoon SJ, Fang YH, Lim CH, et al. Regeneration of ischemic heartusing hyaluronic acid-based injectable hydrogel. J Biomed Mater ResB 2009;91B:163–71.

8. Davis ME, Hsieh PCH, Takahashi T, et al. Local myocardialinsulin-like growth factor 1 (IGF-1) delivery with biotinylated peptidenanofibers improves cell therapy for myocardial infarction. Proc NatlAcad Sci U S A 2006;103:8155–60.

9. Dubois G, Segers VF, Bellamy V, et al. Self-assembling peptidenanofibers and skeletal myoblast transplantation in infarcted myocar-dium. J Biomed Mater Res B Appl Biomater 2008;87:222–8.

0. Lin Y, Yeh M, Yang Y, et al. Intramyocardial peptide nanofiberinjection improves postinfarction ventricular remodeling and efficacy ofbone marrow cell therapy in pigs. Circulation 2010;122:S132–41.

1. Kim JH, Jung Y, Kim SH, et al. The enhancement of mature vesselformation and cardiac function in infarcted hearts using dual growthfactor delivery with self-assembling peptides. Biomaterials 2011;32:6080–8.

2. Liu W, Ashford MW, Chen J, et al. MR tagging demonstratesquantitative differences in regional ventricular wall motion in mice,rats, and men. Am J Physiol Heart Circ Physiol 2006;291:H2515–21.

3. Pilla JJ, Blom AS, Gorman JH, et al. Early postinfarction ventricularrestraint improves borderzone wall thickening dynamics during re-modeling. Ann Thorac Surg 2005;80:2257–62.

4. Blom AS, Pilla JJ, Arkles J, et al. Ventricular restraint prevents infarctexpansion and improves borderzone function after myocardial infarc-tion: a study using magnetic resonance imaging, three-dimensionalsurface modeling, and myocardial tagging. Ann Thorac Surg 2007;84:2004–10.

5. Gepstein L, Ding C, Rehemedula D, et al. In vivo assessment of theelectrophysiological integration and arrhythmogenic risk of myocardialcell transplantation strategies. Stem Cells 2010;28:2151–61.

6. Herpel E, Pritsch M, Koch A, Dengler TJ, Schirmacher P, SchnabelPA. Interstitial fibrosis in the heart: differences in extracellular matrixproteins and matrix metalloproteinases in end-stage dilated, ischaemicand valvular cardiomyopathy. Histopathology 2006;48:736–47.

Key Words: biomaterial y cardiac patch y injectable y left ventricularremodeling y left ventricular restraint y myocardial infarction.

biomaterials for the treatment of myocardial · pdf filebiomaterials for the treatment of ......

Documents