ESC Working Group on Cellular Biology of the

Heart position paper for Cardiovascular

Research tissue engineering strategies combined

with cell therapies for cardiac repair in ischaemic

heart disease and heart failure

Rosalinda Madonna12dagger Linda W Van Laake3dagger Hans Erik Botker4 Sean M Davidson5

Raffaele De Caterina126 Felix B Engel7 Thomas Eschenhagen89

Francesco Fernandez-Aviles1011 Derek J Hausenloy121314151617

Jean-Sebastien Hulot181920 Sandrine Lecour21 Jonathan Leor22

Philippe Menasche232425 Maurizio Pesce26 Cinzia Perrino27 Fabrice Prunier28

Sophie Van Linthout293031 Kirsti Ytrehus32 Wolfram-Hubertus Zimmermann3334

Peter Ferdinandy3536dagger and Joost PG Sluijter37dagger

1Institute of Cardiology and Center of Excellence on Aging ldquoG drsquoAnnunziordquo UniversitymdashChieti Italy 2University of Texas Medical School in Houston USA 3Cardiology and UMCUtrecht Regenerative Medicine Center University Medical Center Utrecht The Netherlands 4Department of Cardiology Aarhus University Hospital Aarhus N Denmark 5The HatterCardiovascular Institute University College London London UK 6University of Pisa Pisa University Hospital Pisa Italy 7Experimental Renal and Cardiovascular Research Departmentof Nephropathology Institute of Pathology Friedrich-Alexander-Universitat Erlangen-Nurnberg (FAU) Erlangen Germany Muscle Research Center Erlangen MURCE 8Institute ofExperimental Pharmacology and Toxicology University Medical Center Hamburg Eppendorf Germany 9DZHK (German Centre for Cardiovascular Research) Partner Site HamburgKielLubeck Hamburg Germany 10Department of Cardiology Hospital General Universitario Gregorio Mara~non Instituto de Investigacion Sanitaria Gregorio Mara~non UniversidadComplutense Madrid Spain 11CIBERCV ISCIII Madrid Spain 12Cardiovascular amp Metabolic Disorders Program Duke-National University of Singapore Medical School Singapore13National Heart Research Institute Singapore National Heart Centre Singapore 14Yong Loo Lin School of Medicine National University Singapore Singapore 15The HatterCardiovascular Institute University College London London UK 16The National Institute of Health Research University College London Hospitals Biomedical Research CentreResearch amp Development London UK 17Tecnologico de Monterrey Centro de Biotecnologia-FEMSA Nuevo Leon Mexico 18Universite Paris-Descartes Sorbonne Paris Cite ParisFrance 19Paris Cardiovascular Research Center (PARCC) INSERM UMRS 970 Paris France 20Hopital Europeen Georges Pompidou AP-HP Paris France 21Hatter CardiovascularResearch Institute University of Cape Town South Africa 22Tamman and Neufeld Cardiovascular Research Institutes Sackler Faculty of Medicine Tel-Aviv University and Sheba MedicalCenter Tel-Hashomer Israel 23Department of Cardiovascular Surgery Hopital Europeen Georges Pompidou Paris France 24Universite Paris-Descartes Sorbonne Paris Cite ParisFrance 25INSERM UMRS 970 Paris France 26Unita di Ingegneria Tissutale Cardiovascolare Centro Cardiologico Monzino IRCCS Milan Italy 27Department of Advanced BiomedicalSciences Federico II University Naples Italy 28Institut Mitovasc INSERM CNRS Universite drsquoAngers Service de Cardiologie CHU Angers Angers France 29Berlin-Brandenburg Centerfor Regenerative Therapies Charite University Medicine Berlin Campus Virchow Klinikum Berlin Germany 30Department of Cardiology Charite University Medicine Berlin CampusVirchow Klinikum Berlin Germany 31DZHK (German Centre for Cardiovascular Research) Partner Site Berlin Berlin Germany 32Department of Medical Biology UiT The ArcticUniversity of Norway Norway 33Institute of Pharmacology and Toxicology University Medical Center Gottingen Gottingen Germany 34DZHK (German Centre for CardiovascularResearch) Partner Site Gottingen Gottingen Germany 35Department of Pharmacology and Pharmacotherapy Semmelweis University Nagyvarad ter 4 III-V Floor H-1089 BudapestHungary 36Pharmahungary Group Szeged Hungary and 37Department of Cardiology Experimental Cardiology Laboratory Regenerative Medicine Center University Medical CenterUtrecht Utrecht University Heidelberglaan 100 3584 CX Utrecht the Netherlands

Received 26 October 2018 revised 21 December 2018 editorial decision 8 January 2019 accepted 10 January 2019 online publish-ahead-of-print 17 January 2019

Abstract Morbidity and mortality from ischaemic heart disease (IHD) and heart failure (HF) remain significant in Europe andare increasing worldwide Patients with IHD or HF might benefit from novel therapeutic strategies such as cell-based therapies We recently discussed the therapeutic potential of cell-based therapies and provided recommen-dations on how to improve the therapeutic translation of these novel strategies for effective cardiac regenerationand repair Despite major advances in optimizing these strategies with respect to cell source and delivery methodthe clinical outcome of cell-based therapy remains unsatisfactory Major obstacles are the low engraftment and sur-vival rate of transplanted cells in the harmful microenvironment of the host tissue and the paucity or even lack of

Corresponding authors Tel thorn31 88 7555555 E-mail jsluijterumcutrechtnl (JPGS) Tel thorn36 1 210 4416 E-mail peterferdinandypharmahungarycom (PF)dagger These authors contributed equally to this work

Published on behalf of the European Society of Cardiology All rights reserved VC The Author(s) 2019 For permissions please email journalspermissionsoupcom

Cardiovascular Research (2019) 115 488ndash500 REVIEWdoi101093cvrcvz010

Dow

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n Libraries user on 26 April 2019

endogenous cells with repair capacity Therefore new ways of delivering cells and their derivatives are required inorder to empower cell-based cardiac repair and regeneration in patients with IHD or HF Strategies using tissue en-gineering (TE) combine cells with matrix materials to enhance cell retention or cell delivery in the transplantedarea and have recently received much attention for this purpose Here we summarize knowledge on novelapproaches emerging from the TE scenario In particular we will discuss how combinations of cellbio-materials(eg hydrogels cell sheets prefabricated matrices microspheres and injectable matrices) combinations might en-hance cell retention or cell delivery in the transplantation areas thereby increase the success rate of cell therapiesfor IHD and HF We will not focus on the use of classical engineering approaches employing fully synthetic materi-als because of their unsatisfactory material properties which render them not clinically applicable The overall aimof this Position Paper from the ESC Working Group Cellular Biology of the Heart is to provide recommendationson how to proceed in research with these novel TE strategies combined with cell-based therapies to boost cardiacrepair in the clinical settings of IHD and HF

Keywords Cardiac tissue engineering bull Ischaemic heart disease bull Heart failure bull Biomaterials bull Cells

1 Tissue engineering and celltherapy are they usefulapproaches

Most complex organisms have lost the ability to fully regenerate theheart However stimuli to reactivate regenerative processes mammaliancells have been identified1 Despite this knowledge we have learnedover the years that reactivation of heart muscle regeneration is muchmore difficult than suggested by earlier studies1 Nature Biotechnologypublished an editorial in 2017 referring to lsquoA futile cycle in cell therapyrsquo2

because of the none-to-marginal benefits of cardiac cell therapy The dis-credit on the entire research area has increased following the emergenceof unreliable publications especially in the infancy of the field by unreli-able unscrupulous scientists simply willing to ride a fashionable horse re-capitulating the story of gene therapy 20 years before All that hasprompted individual scientists declared lsquothe death of this research fieldrsquoYet it is not a novel observation that after an unreasonable hype and aphase of frustration that the true value of scientific discoveries unveilAnd most importantly in light of the huge clinical need it is in our viewfully warranted to further scrutinize the possibility to regenerate the fail-ing heart by remuscularization Obvious roadblocks (eg poor cell reten-tion and lack of proper integration) must be overcome to unfold thetrue potential of novel regenerative treatments For this is important toask What have we learned so far and what needs to be achieved to ob-tain better result In recent years a consensus has been reached on sev-eral aspects that still require attention for the successful implementationof myocardial cell therapy34 To this aim different cell types endowedwith various regenerative activities have been used with various out-comes Currently we consider first-generation clinical cell therapy candi-dates ie cell types that can be relatively easy prepared for clinicalapplications but exhibit limited regenerative potential including bonemarrow-derived mononuclear cells or mesenchymal stromal cells(MSCs) with a focus on stimulation of endogenous regenerativeresponses5 Second-generation clinical cell therapy candidates needmore refined isolation and ex vivo amplification procedures but have ahigher regenerative potential such as several cardiac derived progenitorcells in the form of cardiospheres and pluripotent stem cell-cardiacderivatives including cardiac progenitor cells and cardiomyocytes andare considered more like an exogenous regenerative approach to re-place lost myocardial cells However and irrespective of the cell sourcea major problem for cell therapy is the low level of retention of infused

or injected cell products Indeed although encouraging results havebeen reported most studies concur that only few of the transplantedcells survive in the hostile environment of the host tissue such as thatoccurring after an infarction and even fewer integrate and are retainedin the host myocardiummyocardial scar Transplanted cells quickly dis-appear from the injection site because they simply die in the diseasestruck and thus typically hostile environment or are lsquowashed outrsquo intothe circulation6 The poor cell retention in the receiving tissue is primar-ily related to typically used delivery methods such as intramyocardial(IM) injection anterograde intracoronary perfusion or retrograde deliv-ery via the coronary venous (RV) delivery with short-term engraftmentof approximately 10ndash15 can be detected regardless of the dose ofinjected cells7 long-term engraftment (gt1 month) is reported to be lessthan 16 questioning their direct contribution to myocardial remuscula-rization Irrespective of the cell type a significant fraction of cells (35)localizes to the lungs after IM delivery apparently due to clearancethrough venous myocardial drainage8 MSCs applied attached to smallgelatinous carriers resulted in reduced drainage from the myocardiumcompared with freely suspended MSC controls8 Although suchapproaches are promising initial high cell retentions may be lost whencells detach in time in the myocardium subsequently causing a significantdrop in cell numbers9 More advanced tissue engineering (TE)approaches have led to long-term cell retentions of more than 80 andtherefore have gained much attention in recent years10

The success of TE in the treatment of other medical conditions11

should motivate the continuation of work in the cardiovascular field Inthis position paper we therefore discuss how new technologies such asTEbiomaterials tools can be used to promote the success rate of celltherapies for ischaemic heart disease (IHD) and heart failure (HF) In thiscontext some semantic considerations in terms of TE and regenerativemedicine must be made to better understand how the two fields inter-sect and synergize each other

TE aims at assembling functional constructs that restore maintain orimprove damaged tissues or entire organs through the combined use ofscaffolds cells and biologically active molecules Regenerative medicineincludes TE but in addition also includes research on self-healingmdashwhere the body uses endogenous mechanisms sometimes with the helpof foreign biological materialsmdashto recreate cells and rebuild tissues andorgans TE emphasizes the starting materials and scaffolds used to createde novo tissue implants while regenerative medicine encompasses theformation of new tissue induced by tissue-engineered materials TheCommittee on the Biological and Biomedical Applications of Stem Cell

Tissue engineering and cell-based therapies for cardiac repair in ischaemic heart disease and heart failure 489D

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endogenous cells with repair capacity Therefore new ways of delivering cells and their derivatives are required inorder to empower cell-based cardiac repair and regeneration in patients with IHD or HF Strategies using tissue en-gineering (TE) combine cells with matrix materials to enhance cell retention or cell delivery in the transplantedarea and have recently received much attention for this purpose Here we summarize knowledge on novelapproaches emerging from the TE scenario In particular we will discuss how combinations of cellbio-materials(eg hydrogels cell sheets prefabricated matrices microspheres and injectable matrices) combinations might en-hance cell retention or cell delivery in the transplantation areas thereby increase the success rate of cell therapiesfor IHD and HF We will not focus on the use of classical engineering approaches employing fully synthetic materi-als because of their unsatisfactory material properties which render them not clinically applicable The overall aimof this Position Paper from the ESC Working Group Cellular Biology of the Heart is to provide recommendationson how to proceed in research with these novel TE strategies combined with cell-based therapies to boost cardiacrepair in the clinical settings of IHD and HF

Keywords Cardiac tissue engineering bull Ischaemic heart disease bull Heart failure bull Biomaterials bull Cells

1 Tissue engineering and celltherapy are they usefulapproaches

Most complex organisms have lost the ability to fully regenerate theheart However stimuli to reactivate regenerative processes mammaliancells have been identified1 Despite this knowledge we have learnedover the years that reactivation of heart muscle regeneration is muchmore difficult than suggested by earlier studies1 Nature Biotechnologypublished an editorial in 2017 referring to lsquoA futile cycle in cell therapyrsquo2

because of the none-to-marginal benefits of cardiac cell therapy The dis-credit on the entire research area has increased following the emergenceof unreliable publications especially in the infancy of the field by unreli-able unscrupulous scientists simply willing to ride a fashionable horse re-capitulating the story of gene therapy 20 years before All that hasprompted individual scientists declared lsquothe death of this research fieldrsquoYet it is not a novel observation that after an unreasonable hype and aphase of frustration that the true value of scientific discoveries unveilAnd most importantly in light of the huge clinical need it is in our viewfully warranted to further scrutinize the possibility to regenerate the fail-ing heart by remuscularization Obvious roadblocks (eg poor cell reten-tion and lack of proper integration) must be overcome to unfold thetrue potential of novel regenerative treatments For this is important toask What have we learned so far and what needs to be achieved to ob-tain better result In recent years a consensus has been reached on sev-eral aspects that still require attention for the successful implementationof myocardial cell therapy34 To this aim different cell types endowedwith various regenerative activities have been used with various out-comes Currently we consider first-generation clinical cell therapy candi-dates ie cell types that can be relatively easy prepared for clinicalapplications but exhibit limited regenerative potential including bonemarrow-derived mononuclear cells or mesenchymal stromal cells(MSCs) with a focus on stimulation of endogenous regenerativeresponses5 Second-generation clinical cell therapy candidates needmore refined isolation and ex vivo amplification procedures but have ahigher regenerative potential such as several cardiac derived progenitorcells in the form of cardiospheres and pluripotent stem cell-cardiacderivatives including cardiac progenitor cells and cardiomyocytes andare considered more like an exogenous regenerative approach to re-place lost myocardial cells However and irrespective of the cell sourcea major problem for cell therapy is the low level of retention of infused

or injected cell products Indeed although encouraging results havebeen reported most studies concur that only few of the transplantedcells survive in the hostile environment of the host tissue such as thatoccurring after an infarction and even fewer integrate and are retainedin the host myocardiummyocardial scar Transplanted cells quickly dis-appear from the injection site because they simply die in the diseasestruck and thus typically hostile environment or are lsquowashed outrsquo intothe circulation6 The poor cell retention in the receiving tissue is primar-ily related to typically used delivery methods such as intramyocardial(IM) injection anterograde intracoronary perfusion or retrograde deliv-ery via the coronary venous (RV) delivery with short-term engraftmentof approximately 10ndash15 can be detected regardless of the dose ofinjected cells7 long-term engraftment (gt1 month) is reported to be lessthan 16 questioning their direct contribution to myocardial remuscula-rization Irrespective of the cell type a significant fraction of cells (35)localizes to the lungs after IM delivery apparently due to clearancethrough venous myocardial drainage8 MSCs applied attached to smallgelatinous carriers resulted in reduced drainage from the myocardiumcompared with freely suspended MSC controls8 Although suchapproaches are promising initial high cell retentions may be lost whencells detach in time in the myocardium subsequently causing a significantdrop in cell numbers9 More advanced tissue engineering (TE)approaches have led to long-term cell retentions of more than 80 andtherefore have gained much attention in recent years10

The success of TE in the treatment of other medical conditions11

should motivate the continuation of work in the cardiovascular field Inthis position paper we therefore discuss how new technologies such asTEbiomaterials tools can be used to promote the success rate of celltherapies for ischaemic heart disease (IHD) and heart failure (HF) In thiscontext some semantic considerations in terms of TE and regenerativemedicine must be made to better understand how the two fields inter-sect and synergize each other

TE aims at assembling functional constructs that restore maintain orimprove damaged tissues or entire organs through the combined use ofscaffolds cells and biologically active molecules Regenerative medicineincludes TE but in addition also includes research on self-healingmdashwhere the body uses endogenous mechanisms sometimes with the helpof foreign biological materialsmdashto recreate cells and rebuild tissues andorgans TE emphasizes the starting materials and scaffolds used to createde novo tissue implants while regenerative medicine encompasses theformation of new tissue induced by tissue-engineered materials TheCommittee on the Biological and Biomedical Applications of Stem Cell

Tissue engineering and cell-based therapies for cardiac repair in ischaemic heart disease and heart failure 489D

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Research (httpswwwncbinlmnihgovbooksNBK223688) stated thatin the new era of TE combined with regenerative medicine lsquoregenerativemedicine seeks to understand how and why stem cells whether derivedfrom human embryos or adult tissues are able to develop into special-ized tissues and seeks to find new ways of applying cells and their deriva-tives in order to empower cell based repair and regeneration that willrestore lost function in damaged organsrsquo Therefore for the purpose ofthis Position paper we will discuss on TE as a strategy that can help theregenerative process initiated by the cellular component providing abiomolecular and spatial environment conductive to cell survival prolif-eration and vascularization aimed at supporting cell and tissue growthWe will focus on how biomaterials in combination with a cellular com-ponent (culture systems or cell products) can be used to increase thesuccess rate of cell therapies for IHD and HF by inducing reparativeprocesses

2 Major properties andrequirements of cell types

Cardiac cell-based TE aims to remuscularize post-infarct myocardialscars provide paracrine support for activation of endogenous repairmechanisms and add substitute tissue for failing hearts using a three-dimensional approach Depending on the specific therapeutic goal thecell requirements vary and different cell types are needed If the primaryobjective is remuscularization a large number of bona fide cardiomyo-cytes are required which eventually couple with endogenous cardio-myocytes The general feasibility of cardiomyocytes engraftment withelectromechanical integration was demonstrated earlier for foetal12 andpluripotent stem cell derived13 cardiomyocytes as well as engineeredheart muscle (EHM)14 allografts using either voltage indicator dyes andtwo-photon imaging or multi-array electrode recordings of the epicardialspread of electrical excitation Murry et al15 pioneered the use of geneti-cally encoded calcium indictors to demonstrate electrical coupling ofhuman ES-cell-derived cardiomyocyte grafts in injured guinea-pig andnon-human primate16 Whilst the original studies in only mildly injurednon-human primate demonstrated ventricular arrhythmias in all investi-gated animals16 recently published data suggest a lower risk of ventricu-lar arrhythmias and ectopy rather than re-entry as the underlyingmechanism17 In case of activation of host-associated repair pathways viaparacrine signalling the flexibility of cell type is greater TE is here mainlydirected at optimizing the early cell retention which allows the releaseof paracrine factors a strategy which might later be replaced by the ad-ministration of their secretome only18 Independent of the objective thecells used for TE should be compliant with the lsquoGuideline on human cell-based medicinal productsrsquo from the European Medicines Agency relatedto the identity of the cell population potency purity viability safety effi-cacy and suitability for intended use For more details see ref4

21 Cells and their requirements forTE-directed remuscularizationWith the advent of human pluripotent stem cells (hPSC) including hu-man embryonic stem cells (hESC) and human induced pluripotent stemcells (hiPSC) the availability of large-scale production in bioreactors anddifferentiationpurification protocols sufficient quantities of essentiallypure human cardiomyocytes can be produced according to GMPrequirements and applied in the engineering of heart muscle19

Human EHM rings and patches19ndash21 as well as human engineeredheart tissue strips22 from human embryonic (hESC)- and hiPSC-derivedcardiomyocytes could be implanted and used to partially repair largemuscle defects in rat and guinea-pig hearts These studies collectivelydemonstrated long-term cardiomyocyte retention (gt200 days) matura-tion graft vascularization and a variable degree of proliferation furtherelectrical coupling to the host myocardium was observed in some butnot all investigated guinea-pigs22 in line with earlier studies demonstrat-ing the isolation of human engineered muscle xenograft grafts by scarformation in athymic rats23 Three-dimensional culture and maturationof hiPSC-cardiomyocytes can be stimulated in clinical scalable 3D cul-tures displaying robust electromechanical coupling consistent H-zonesI-bands and evidence for T-tubules and M-bands and there is a generalagreement that engineered three-dimensional heart muscle culturesachieve a greater resemblance to bona fide human myocardium in com-parison to standard 2D monolayer cultures212224ndash33 Several specificinterventions have been identified to improve the maturation of hPSC-derived cardiomyocytes including (i) addition of thyroid hormone34

(ii) application of electrical stimulation333536 (iii) mechanicalloading212737ndash39 or (iv) co-culture with cardiac-specific cell types includ-ing endothelial cells22 and cardiac fibroblasts213140ndash42 or a mixture offibroblast-like stromal cells3743 A good understanding of the optimalcellular make up as well as reliable quality markers for cardiomyocytesand non-myocyte maturation should be instrumental to further improvethe sophisticated architecture and function engineered myocardium

Current protocols mainly give rise to ventricular-like cardiomyocytesGoing forward the field would benefit from the development of precisedirected standardized protocols for cardiomyocytes subtype specifica-tion and functional maturation Accordingly several steps have beentaken including the formation of atrial myocytes specification44 epicar-dial progenitor cells4546 and sinoatrial node cells47 Recently protocolsfor the engineering of EHM with distinct atrial and ventricular propertieshave been reported48 Non-cardiomyocytes are included in most TEstudiesmdasheither by their addition or by a contamination of the cardio-myocyte pool Whether and in particular how they contribute to tissueassembly maturation and survival after implantation needs furthermechanistic studies It seems clear that endothelial cells can supportangiogenesis49 and fibroblasts contribute to extracellular matrix (ECM)homeostasis as well as its viscoelastic properties21 In addition there iscertainly paracrine cross-talk which may be instrumental in the heartmuscle tissue formation process

Additional open questions include Are there any circumstances inwhich non-cardiomyocytes can be damaging to graft or host Is there anideal mixture of cardiomyocytes with the multiple stroma cell speciesfound in the healthy heart Recently Gao et al50 reported the use of hu-man induced PS derived cardiomyocytes (hiPSC) smooth muscle cells(hiPS-SMC) and endothelial cells (hiPS-EC) that were mixed into a fibrinscaffold for 7 days to create a cardiac muscle patch The patch was usedto cover an infarct area in a pig heart Beneficial effects likely mediatedby paracrine cross-talk were observed after 4 weeks50 It is clear thatthe proximity between capillary endothelial cells and cardiomyocytes inthe healthy adult heart has a functional role beyond lining of the capil-lary51 which includes pro-angiogenic paracrine signalling52

22 Cells and their requirements forTE-directed endogenous regenerationCells committed to a cardiac lineage such as right ventricle-derived car-diosphere-derived cells53 bone marrow-derived MSC engineered to

490 R Madonna et alD

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express cardiac transcription factors54 and ESC-derived cardiac progeni-tor cells55 may be used in TE to stimulate endogenous regeneration bythe release of paracrine factors ESCiPSC-derived cells carry the risk ofteratoma formation due to contamination with residual pluripotent cellsthat have not responded to lineage-specific instructive cues and there-fore have retained their state of uncontrolled proliferative potential Toavoid this contamination a selection step based on surface antigens ismandatory for obvious safety reasons56 From a translational point ofview a more realistic approach is to control the differentiation and prolif-eration processes properly to exclude the presence of teratogenic cellsWith regards to the prediction of the efficacy of cells to be used for TE acardiopoietic index was recently established57 This biomarker-based in-dex relies on canonical cardiac transcription factors employing gene ex-pression profiles as a means to assess the regenerative quotient ofpatient-derived cells

23 Allogeneic vs autologous cellsThe use of allogeneic cells is preferential over autologous cells since theyare not exposed to patient risk factors (ie age diabetes mellitus andsmoking) known to impair the potential of autologous stem cells58 andallow off-the-shelf use streamlined logistics consistency and immediateavailability of the product and guaranteed dosage However allogeneiccells will always induce an immune response Alloreactivity depends onforeign peptide presentation by major histocompatibility complex(MHC) on antigen presenting cells and detection by T cells59 and can bemodulated by T cell suppressors including calcineurin inhibitors (cyclo-sporine and tacrolimus are commonly used) and corticosteroidsImmunosuppressive treatment is associated with a number of unwantedeffects including hypertension due to kidney damage transaminitis dueto liver damage an increased risk for infections and if used long termwith malignancies) These are the same risks heart transplant patientsare exposed to and have been proven to be manageable An alternativestrategy to avoid the need for long-term immunosuppression is modula-tion of the innate immune system A very recent paper from Brazaet al60 demonstrated the feasibility of promoting long-term organ trans-plant acceptance by inhibiting macrophage activation with nanotherapeutics

Another strategy to prevent allogeneic cell transplantation-related im-mune rejection is the use of MHC-matched donor cells or to engineergrafts with immune tolerant properties such as recently demonstratedby a functional HLA knock-out via beta-2-microgbulin (B2M) deletionwith subsequent insertion of a B2M-HLA-E fusion to overcome T- andNK-cell mediated killing61 Although similarly appealing as autologouscells from the immunology point of view these cells will be more difficultto eradicate if unwanted side effects occur because they will not bedetected as foreign by the endogenous immune system A potentialstrategy for eradication of immune tolerant cells is the use of suicidegenes as pioneered by Malcom Brenner and Helen Heslop for treatmentof graft vs host disease following adoptive cell therapy62

Systematic review and meta-analysis of cell therapy in large animalstudies concluded effects of autologous and allogeneic cell therapy forIHD were similar irrespective of immunosuppressive therapy63 whichcan be taken as an additional indirect evidence for a similar cell loss withpredominantly paracrine mechanisms of action in the reported studies

In the context of TE strict immunologic monitoring as well as for ex-ample monitoring circulating cell-free allograft DNA64 will be helpful toif needed adapt immune suppression protocols for enhanced graft sur-vival It appears likely that a differentiated use and need for

immunosuppressive therapy and MHC matching will depend also on thecell type and TE approach used

For a TE strategy directed at stimulating cardiac endogenous regener-ation via paracrine effects a short-term immunosuppressive treatmentwould be recommended with the premise that the transplanted cellswould be likely short-lived and act via paracrine signalling18 This short-term immunosuppressive regime is underscored by the finding that al-though allogeneic cells are expected to be eliminated more rapidly thanautologous cells their transient presence shortly after transplantation issufficient to yield equivalent long-term benefits65 In the case of TE-directed remuscularization with iPS- or ESC-derived cardiomyocytesdurable engraftment of the cellsgraft is required along with long-termstate-of-the-art immunosuppressive therapies MHC matching of iPS-derived cardiomyocytes has been shown to enhance cell engraftment innon-human primates66 Translated to patients a large repository with avariety of MHC-homozygous stem cell lines collected from donors orengineered may solve this issue67

3 Methods for engineeringmyocardial tissue

As indicated major hurdles to therapeutic applications have been ob-served including low cellular survivals and poor localization to the targetarea To further facilitate integration and prolonged activities severalapproaches are under development that each have various propertiesand advantages These approaches include (i) seeding of cells on pre-formed scaffolds (ii) self-assembly of cells in hydrogels and (iii) cell sheetengineering (reviewed in ref6869)

31 HydrogelsHydrogel-based injection and TE are promising techniques in which hy-drophilic structures are used made of either synthetic or natural poly-mers which can assemble into a three-dimensional polymericnetwork70 Hydrogels have a high number of essential scaffold require-ments including the exchange of oxygen nutrients and metabolites dueto their porosity and the possibility of including growth factors and othermolecules to mediate cross talk between cells71 However in generalthe hydrogel structures lack structural supportive characteristics and thecorrect stiffness of cardiac materials72

32 Engineered myocardial tissueEngineered myocardial tissue can be used to aim at the restoration andimprovement of cardiac function in terms of tissue regeneration as indi-cated above however they can also be used to develop three-dimensional in vitro models able to mimic the native heart muscleConstruction of engineered heart tissuemuscle (EHTM) was pioneeredand continuously developed by the laboratories of Eschenhagen andZimmermann2173ndash76 and became widely used recently4977ndash79 To thisend a range of innovative three-dimensional culture in vitro systems forcardiac disease modelling has been developed In both approaches over-lapping characterizations are needed including the presence of (i) native-like biochemical electrophysiological and mechanical cell-ECM and cellndashcell interactions (ii) dynamic in vivo like conditions such as fluid flow andshear stress and (iii) correct cell characteristics and morphologies andstructural micro-architectures

Tissue engineering and cell-based therapies for cardiac repair in ischaemic heart disease and heart failure 491D

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33 Extracellular matrixIn addition to the cellular components of myocardial tissue the ECM is amajor player in normal cardiac functioning and homeostasis and cellularbehaviour Ideally a hydrogel or engineered construct should perfectlymimic native cardiac ECM and provide a physiological micro-environment for cells The cardiac ECM consists of a complex networkof structural and non-structural (matricellular) proteins of which three-dimensional hydrogel scaffolds have been generated from decellularizedcardiac ECM80 and used as injectable biomaterial for myocardial repair81

currently under clinical investigation (NCT02305602)In addition to the native cardiac ECM naturally occurring ECM pro-

teins are suitable materials to be used as a hydrogel-based scaffold in car-diac TE due to their bio-mimicking and bioactive properties82 Some ofthe frequently used hydrogels from natural sources include collagen21

fibrin35 gelatin83 hyaluronic acid84 and alginate10 Matrigel was originallyintroduced as being supportive in the engineering of rat EHT76 with alsosubsequent application in human TE but will not be applicable in clinicalapplications

While the primary advantage of these materials is to maintain trans-planted cells alive in the myocardium and retain them in situ followingtransplantation a potential shortcoming is the possibility that even smallmodifications of local mechanical compliance could activate fibrosis dueto the emerging stiffness-sensitivity of myocardial resident stromalcells85 This problem may be overcome by finely controlling the visco-elastic properties of the materials employed to encapsulate cells or byproviding them with sufficiently controlled level of degradation to avoidchanges in myocardium compliance In this respect employment of lsquobio-inkrsquo materials such as gelatin methacryloyl (GelMA) hydrogels whosestiffness may be easily adjusted by eg pre-injection photo-polymer-ization86 offer a new opportunity for advanced myocardial TEapplications

34 Cell sheetsAlternatively non-cardiomyocytes can be employed for endogenousECM production resulting in a replacement of exogenous scaffold mate-rial87 Similarly in cell sheet engineering88 it is well established that cell-secreted ECM plays a key role in sheet assembly and epicardial connec-tion after implantation89 Cell sheet engineering makes use oftemperature-responsive polymer surfaces to enable the controlled re-lease of cell monolayers free-floating sheet of cohesive cells that can forexample be placed onto the epicardium with or without stiches89 Usingthis approach 3ndash4 monolayers can be fused without a palpable core ne-crosis The cell sheet approach can be applied to all cell types which arecapable of forming a biomechanically interconnected monolayer such ascardiomyocytes for contractile support and non-myocytes for the deliv-ery of secreted factors90ndash92 This technology has been recently testedclinically for the delivery of skeletal myoblasts to the failing humanheart93 and is presently further exploited for the delivery of allogeneiciPSC-derived cardiomyocytes94 Issues with this approach are the frailtyof these sheets which may cause their folding or tearing during manipula-tions and the limited number of sheets which can be stacked on eachother without cell death95

35 BiofabricationThe major concern with classical TE which entails the seeding of pre-fabricated scaffolds with cells is that only inhomogeneous cell densitiescan be achieved because of the cells propensity to remain at the scaf-folds surface and thus only weakly contracting cardiac tissues can be

fabricated This caveat may not apply to the delivery of non-cardiomyocytes with a primary mode of action related to their paracrineactivity In hydrogel approaches cell content is typically more homoge-neous and anisotropic growth is typically guided by mechanical stimuliA better understanding of how to achieve dense anisotropic musclestructures with capillarization would be important for the developmentof the next generation of tissue-engineered products Accordingly tre-mendous effort is invested into improved biofabrication technologiescombining additive manufacturing techniques with cell printing to createhierarchical tissue-like structures commonly known as three-dimensional printing9697 In principle biofabrication allows the produc-tion of cardiac tissues layer by layer utilizing multiple print heads and inks(eg shear thinning gels) containing distinct cell-types In this way variousparameters can be controlled such as correct cellular composition thepositioning of various cell-types and materials vascularization and the in-corporation of bioactive substances98 Currently the field focusses onimproving the hardware to provide more additional gels for printingand to include materials that can change their shape after printing upondefined stimuli (4D biofabrication) to generate for example vascular-likenetworks99100 Although promising and potentially very versatile in itsapplicability it remains a key challenge to printing tissues at meaningfuldimensions for heart repair applications

4 How biomaterials and myocardialengineering can influence celltherapy in the repair andregeneration of the heart

Two substantially different strategies can be endeavoured in myocardialTE (i) cell-based methods in which differentiated myocardium tissuepatches or progenitor cells lsquonichesrsquo can be implanted directly in areaslacking contractile tissue or (ii) in situ strategies in which composite bio-materials (cells thorn ECM) may be designed to support the regenerationcapacity of endogenous myocardial cells

41 Cell-based methodsFor clinical translation the first discussed strategy requires not onlyfine-tuning of materialscells combinations to recapitulate the physiol-ogy of the normal tissue environment but also an enhancement of thepropensity for electromechanical and vascular coupling with the re-cipient myocardial tissue The latter aspect is crucial to promote sta-ble patch engraftment and coordinated action potential propagationfrom pre-existing myocardium (reviewed in ref80) A second probleminherent to the generation of myocardial patches concerns the statusof cell maturity inside the engineered grafts Commonly used stem orprogenitor cell derivatives have a variable level of proliferation andphenotypic immaturity which results in the formation of rather imma-ture muscle in vitro Maturation occurs after implantation in vivo ren-dering the cells indistinguishable from native myocardium in anallograft setting13 Whether similar factors would drive human cardio-myocyte maturation in the diseased heart remains an open questionData on advanced maturation after implantation even in a xenograftsetting suggest that similar maturation capacities exist in human PSC-derived cardiomyocytes1969 The underlying process of in vivo matura-tion are however not well understood and further optimization of en-gineering paradigms may benefit from further mechanistic insight Apossible implementation of engineering systems to overcome these

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shortcomings may consist in using biomaterial fabrication criteria sup-porting coordinated multi-layered vascular and myocardial cellgrowth100 systems favouring electro-mechanical coupling of cells inthe patch101102 and finally materials with defined biophysical charac-teristics (eg stiffness) promoting maturation of myocyte action po-tential propagation103

An emerging area of interest in myocardial engineering is themodelling of the so-called cardiac niches which can be defined as indi-vidual lsquofunctional unitsrsquo that include spatially prearranged biochemicalbiophysical information These functional units can instruct thecoordinated differentiation of stemprogenitor cells into terminallydifferentiated cardiomyocytes while maintaining stable amounts ofself-renewing cells in its core104 By exploiting the natural stempro-genitor cardiogenic differentiation process this strategy may lead to anew lsquoorganoidrsquo-based approach to cardiac (re)generation105 In casestandardization and scalability will be demonstrated this methodcould be employed to produce large amounts of allogenic or evenpersonalized tissue lsquobuilding blocksrsquo that could be transplanted intothe recipient myocardium using appropriate delivery systems Trans-endocardial injection guided by real-time electrophysiology myocar-dial mapping (eg NOGA4) is an example of delivery systems with thecaveat that endocardial deliveries of a bulk material need a carefulsafety assessment because of the potential of systemic embolizationof the material end-products An alternative without this limitation isthe percutaneous delivery of tissue-engineered products with ashape-memory onto the epicardium106

42 In situ strategiesA systematic investigation of the conditions promoting stemprogenitorcells cardiogenic differentiation could either lead to improved existingregenerative approaches by lsquocombiningrsquo materialscells or even cell-freein situ strategies A first possibility is offered by embedding therapeuticcells into unstructured biomaterials (eg hydrogels) and combining themwith survivalcardiogenic factors which may preserve their vitality prolif-eration andor enhance differentiation capacity in the potentially hostileenvironment107 In a second formulation the injection of lsquosmartrsquo materi-als that instruct in situ cellular specifications has been demonstrated atleast at a proof of concept level108 In this formulation the therapeuticapproach could consist of hydrogels containing instructing signals for car-diac cell reprogramming (eg slowly releasing miRNAs109) or stem cell-derived secretome survival factors110 In the case where the combinationof materialsbioactive factors includes formulations with stiffness charac-teristics consistent with myocardium elasticity111 materials making themelectrically conductive102112 or topologically arranged substrates113

there will be valuable options to operate cell-free cardiac regenerationthat could lead to the delivery of clinically effective therapies In factthese applications would not only boost the inefficient myocardium re-generation process114 but would also permit a coordinated andspatially-organized regeneration of myocardial contractile tissue in areaswhere cardiomyocyte death and myofibroblast-dependent fibrosis typi-cally limit the replacement with new contractile cells In this regard theinclusion of materials (eg silk-derived proteins115) or drugs (eg anti-inflammatory molecules116) capable of suppressing pathways mediatingthe early inflammatory response leading to myofibroblast activation inresponse to myocardium damage or of stimulating cardiomyocyte cell-cycle re-entry in the myocardium116117 could be effective enhancementstrategies limiting the extent of post-ischaemic damage and at the sametime promoting cardiac regeneration

43 How to prevent inflammatoryimmunereactions in the host environmentOne of the most important challenges in the field of cardiac TE is toavoid adverse foreign-body host immune response to implanted scaf-folds Novel biocompatible immunomodulatory biomaterials can reducethe foreign-body response and improve engraftment118 Furthermorebecause inflammation is a critical component influencing cardiac regener-ation118119 immunomodulation by smart biomaterials is a potentialstrategy to overcome this major challenge in cardiovascular regenerativemedicine The modification of the physicochemical properties of bioma-terials can modify the host inflammatory response which can improvebiomaterial integration and their interaction with immune cells includingthe reparative cells such as macrophages and MSC as well as the con-trolled delivery of anti-inflammatory small molecules and cytokines118

5 Cell-free (secretome) approaches

51 Acellular biomaterialsThese cell-free materials include the use of material itself for directingcardiac responses or as delivery vehicles for biologics The material istypically natural (eg alginate collagen hyaluronic acid chitosan decellu-larized ECM) or less commonly a synthetic polymer (reviewed inref120) The proposed mechanisms of benefit include reduction of wallstress by mechanical support and modulation of host cellular responsesincluding inflammation neovascularization fibroblast activity stem cellrecruitment and protection against cell death The potential advantagesof this approach are that it is cost-effective localized (vs systemic) andavoids the need to consider cell survival in the injected biomaterial Themethod of delivery is an important factor with injectable methods thathave the advantage of a minimally invasive delivery route though theneed for injection confers several design limitations on the gels120 Todate results of the few clinical trials of acellular biomaterials have beenmixed121ndash123 Another promising approach is the injection ofVentriGelTM (Ventrix) an injectable hydrogel derived from porcinemyocardial ECM which showed benefits in pigs81 and is currently in aPhase I clinical trial in patients with HF post-myocardial infarction (MI)(NCT02305602)

Biomaterials can be used to deliver biologics such as growth or sur-vival factors This places further limitations on the biomaterial necessi-tating carefully controlled rates of degradation and release In asuccessful example an epicardial collagen patch was used to deliver re-combinant follistatin-like 1 (Fstl1) stimulating cardiomyocyte prolifera-tion and improving cardiac function and survival in mouse and swinemodels of myocardial infarction124 To improve the localization and re-tention in the heart once the factors are released the biomaterial can bemodified to bind the factors This approach has seen some success insmall and large animals120 but clinical translation may be limited by theexpense of synthesizing and incorporating peptide growth factors

52 Exosomes and microvesicles withbiomaterialsThe secretome of stem cells contains a rich cocktail of growth factorsand other pro-regenerative molecules including extracellular vesicles(EVs) such as exosomes and microvesicles125 In fact the secretome maymediate much of the benefit in cardiac function that has been observedafter the injection of stem cells into the heart via mechanisms that in-clude paracrine stimulation of pro-angiogenesis pathways alterations of

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macrophage phenotype and anti-fibrotic effects3126 In a recent head-to-head comparison EVs from human cardiovascular progenitors outper-formed the cells themselves at improving cardiac function in mice withHF post-MI127 Although some long-lasting benefits have been observedafter a single injection of EVs it may be presumed that controlled releaseof the secretome from an injected biomaterial would allow for maximumandor prolonged benefit128 Although there are few studies using thisapproach to date its feasibility has been demonstrated by the use of a hy-drogel based on polyethylene glycol (PEG) end-modified with ureido-pyrimidinone moieties to deliver growth factors in the soluble phasewith no exosome delivery to pig myocardium129130 A gelatin and lapon-ite nanocomposite hydrogel has been used to deliver the completesecretome of human adipose-derived stem cells (hASC) to the peri-infarct myocardium of rats and was found to reduce relative infarct sizeafter 21 days recovery and significantly improve EF110 Finally in a smallfeasibility study in patients hESC-derived cardiovascular progenitorswere encapsulated in a fibrin patch which was then sewn to the epicar-dial surface of the hearts of six patients with HF Although this was asafety study an improvement in cardiac regional systolic contractile func-tion was seen which was most likely mediated via secreted paracrinefactors55

6 Modes of cell applications andretention with biomaterial carriers

61 In vitro and in vivo engineering and thethree routes of cell deliveryThe ideal strategy to deliver cells in biomaterial carriers depends on mul-tiple factors including features of the diseased heart (type of cardiomy-opathy location of scarring) the clinical setting [eg whether or not it iscombined with coronary artery bypass grafting (CABG)] biomaterialcharacteristics and to a lesser extent cell characteristics The actual TEprocess can take place in vitro where the cells are seeded or grown into apre-formed structure or in vivo after injection of cells in conjunction witha biomaterial The stimulation of endogenous repair by transplantedcells or the direct reprogramming of other cell types into cardiomyo-cytes is sometimes also referred to as in vivo TE

IM injection can be performed via the endocardial or epicardial routeThe epicardial route is the only one that allows direct visualization andtherefore usually used in preclinical (small animal) research or in combi-nation with open chest surgery most often CABG for ischaemic cardio-myopathy The endocardial application via a percutaneous approach isless invasive and allows for precisely targeted therapy if a special electro-mechanical mapping system (eg NOGA) is used although these map-pings have their limitations in their anatomical visualizations Thetransvenous approach represents a combination of the two techniquesas cells are injected through a coronary vein puncture131 underIntraVascular UltraSound guidance IM injection thus has the advantageof delivery to a specific location but the risk of rapid wash-out of cells viavenous drainage is high8 and should be overcome with suitablebiomaterials

The epicardial application can also be in the form of an engineered tis-sue patch that is sutured on top of the heart This ensures an excellentcell retention mechanically but electromechanical integration via thisroute may be more challenging and the technique currently depends onopen chest surgery Future technical developments should allow for lessinvasive epicardial (and potentially endocardial) application parallel with

developments in minimal invasive valve surgery Intracoronary infusion isminimally invasive and easy to perform with standard catheterization labequipment but caution should be taken not to induce embolization es-pecially when thicker biomaterials are used In addition the coronary ar-teries may be inaccessible due to the nature of the disease Theinterstitial retrograde coronary venous infusion may then serve as an al-ternative It is performed by placing a balloon-catheter in the coronary si-nus or one of the coronary veins and occluding the distal sidetemporarily to allow the cells to disseminate into the heart132 In eachcase the cells need to be able to migrate across the microvascular endo-thelium to reach their planned site of action Finally because repeateddosing may be required to achieve a maximal therapeutic benefit133 lessinvasive approaches likely need to be considered and in this setting itmight be worth further investigating the intravenous route

62 Injectable hydrogelsNon-gelated switchable hydrogels can be administered using a syringeand incorporated into any catheter-based application Cells and addi-tives such as growth factors are suspended in or co-injected with the liq-uid material provided it features visco-elastic properties allowing it totake a liquid form as the shear stress increases The solution should bedesigned to polymerizecrosslink quickly after arrival in vivo in the heartusually due to pH or temperature change and remain stable afterwardsto prevent embolization Degradation should occur without toxicbyproducts131 This has been reported to enhance cell retention signifi-cantly and possibly improve differentiation and functional effects in pre-clinical models107

63 Porous scaffoldsTherapeutic cells can be grown into a three-dimensional construct on aporous or fibrous scaffold which usually needs additional treatment tomaximize cell attachment69 In cell sheets usually cardiomyocytes orprogenitor cells are combined with support cells which enhance tissueorganization and robustness134ndash136 Until now patches have been placedon the epicardial side of the myocardium via open chest surgery but thedevelopment of less invasive techniques may change this requirement inthe future

64 MicrocapsulesSized in the order of hundreds of microns or less microcapsules consistof cells encapsulated with nanoporous materials137 The capsules pro-tect the cells from recognition by the immune system and may enhancethe long-term paracrine action of the transplanted cells Although intra-coronary infusion of encapsulated glucagon-like peptide-1-eluting mes-enchymal stem cells preserved left ventricular function in a porcinemodel of acute MI the suggestion of coronary occlusion halted thesepreclinical studies For cardiac applications biodegradable hydrogelssuch as gelatin seem most appropriate9 So far application has been viaIM injection due to the size of the cell-laden capsules and the necessityto pass the endothelial barrier in intravascular routes On top of micro-capsules or carriers also (mixed) aggregates138 of iPSC-cardiomyocytesin capsules is a potential route to improve cellular retention and therebyincrease myocardial function139

7 Towards clinical applications

The clinical use of tissue-engineered constructs in myocardial regenera-tion is still at an early phase Although the regulatory framework needed

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to achieve authorization of a tissue engineering product is similar to thatof cell-based therapy the combination of cells and materials in an ad-vanced therapy medicinal products will require more stringent qualitycriteria and therefore more advanced preclinical testing before it can beapproved This includes a careful assessment of potential benefits andobvious risks in a well-defined patient population and ultimately also eco-nomic considerations136140

71 Factors influencing resultslimitationsIn fact although effective carrier materials andor engineeringapproaches may enhance cell or tissue retention the problems withsources of autologous cell and survival in the host tissue remains prob-lematic similarly to any cell-based therapies The quality and number ofcells may diminish in patients who are older or have comorbidities (to-gether with specific medications for the comorbidity) or genetic defectsMoreover celltissue survival is also effected by the host tissue environ-ment with comorbidities aging gender etc (for review see ref3)Unfortunately little is known about the effect of major comorbiditiesand risk factors on quality of cell source and cell survival in the hosttissue141142

Other limitations are the logistics and high costs of such advancedtherapy medicinal products as well as the failure of many biomaterials tomeet translationally relevant requirements The first in man phase onetrials using products of TE will require dedicated GMP-production andclinical infrastructure for the implantation procedure and follow-upGMP-production according to the relevant regulatory demands wouldfor preclinical trials ideally be at one site to ensure quality and compara-bility of a TEP This will be particularly important in case of multicentrestudies This requires qualified protocols and carriers for TEP delivery tothe point-of-care In this context recent data on transatlantic shipping ofEHM without an apparent loss in potency and quality is encouraging19

Early clinical trials would also in light of the high costs associated with theset-up of GMP-production clearly be facilitated by single productionunits If later phase clinical testing and market authorization is consideredbased on compelling clinical data production logistics will have to bereconsidered A general concern is related to the high cost of advancedtherapy medicinal products in general leading to their withdrawal fromthe market despite approval by the European Medical Agency (EMA)and no safety or efficacy concerns143 Thus setting up cost effective pro-duction processes will be at least as important as compelling data fromclinical trials

72 Potential risks arrhythmias tumourdevelopment rejection calcificationSince myocardial tissue is subject to the coordinated propagation ofelectromechanical stimuli the development of arrhythmias is a key riskfor all cell therapeutics and especially so for conductive myocyte-containing therapeutics This caveat has been clearly recognized as clini-cally relevant in the first clinical trials on skeletal muscle cells for heartremuscularization144 A number of important preclinical large animalstudies have further underscored this risk in case of the application ofcardiomyocytes16145146 Conversely a recent study on fibrin-patch me-diated delivery of ESC-derived cardiac progenitors did not provide evi-dence for arrhythmia18 which is in line with the primarily secretomeassociated mechanism of action but also suggests that avoidance of IMpunctures may mitigate the risk of uneven integration of the grafted cellsand the attendant predisposition of inhomogeneous coupling at thegraft-host interface to trigger arrhythmias

Potential risks that could constitute a serious obstacle to the clinicaltranslation of tissue-engineered myocardium could arise from uncon-trolled proliferation and unwanted differentiation of cells in the con-structs that may lead to eg tumour formation in case of iPSCESC147148 or to calcification of the host myocardium by MSC148 Theseissues remain essentially the same as those of classical cell-based cardio-myoplasty approaches with the caveat that an increased efficiency of cellsurvival and engraftment resulting from embedding cells into hydrogelsor structured tissue patches could enhance the risks of side effectsAnother relevant issue that may need to be solved is the problem ofimmune-rejection against cellsmaterials combinations In this regard thematerials causing no inflammatory or foreign body reactions would beideal (reviewed in ref149) This class of materials includes (i) naturally de-rived polymers with an innate anti-inflammatory activity (eg silk) (ii)ECM matrix components deriving from decellularization orlyophilization procedures or finally (iii) materials with controlled releaseof anti-inflammatoryimmune-suppressive molecules A final strategywhich can be used for cardiac TE with allogenic cells could derive fromthe exploitation of cell combinations that maximize the suppression ofimmune responses in vivo150

73 Safety regulatory and ethicalframeworks related to the use of tissueengineering products in myocardial repairAccording to the EMA classification (EC No 13942007) tissue-engineered constructs and combinations of cellsbiomaterials fall in thedefinition of advanced therapy medicinal product A conceptually similardefinition (Human Cells Tissues or Cellular and Tissue-Based ProductsHCTPs) is adopted by the Food and Drug Administration in UnitedStates151 In either cases the adoption of stringent quality criteria comply-ing with the Good Manufacturing Practice (GMP) production under amanufacturing authorization by the local competent authority is the basisto ensure standardization safety traceability and potency of the finalproduct Recognizing the diverse nature of advanced therapy medicinalproducts including the tissue-engineered products (TEP) EU guidelines(eg Guidelines on Safety and Efficacy Follow-up Risk Management ofAdvanced Therapy Medicinal ProductsmdashEMEA1499952008) provideguidance as to how to (i) ensure quality of the production process (ii)evaluate potential risks and (iii) demonstrate potency and efficacy of thefinal product with in vitroin vivo tests Issues that are particularly recog-nized include (i) lsquotransmission of infectious agents to the patient and to closecontactsrsquo (ii) lsquograft dysfunction andor rejectionrsquo (iii) lsquoinduction of autoimmunityor immunogenic reactionsrsquo (iv) lsquoinduction of malignanciesrsquo and (v) lsquoimpossibilityof discontinuing or removal of the productrsquo In case of cellmaterials combina-tions the same guideline additionally recommends specific testing ofbiodegradation and mechanical factors thus asking for an evaluation oflong-term patientgraft interactions possibly affecting the graft perfor-mance at long term These latter recommendations may be particularlyimportant for setting myocardial therapy using for example cellularizedpatches These patches should alternatively be produced with fully bio-absorbable materials able to release therapeutic cells without eliciting in-flammatory responses secondary to material degradation or be designedto resist to biodegradation thereby prompting a full functional integrationin the hostrsquos myocardium Finally each TEP has to be evaluated by the re-sponsible regulatory authority to specify the required manufacturing andpreclinical strategy before embarking on first-in-patient trial

At the time of the preparation of our current paper the availableEMA lsquoScientific Recommendationsrsquo lists (wwwemaeuropaeuemain

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dexjspcurl=pagesregulationgeneralgeneral_content_000301jspampmid=WC0b01ac05800862c0) the following advanced therapy medicinalproducts for myocardial regeneration such as eg autologousallogenichematopoietic stem cells (CD34thornCD133thorn) adult bone marrowadi-pose tissue- or placental (Wharton Jelly)-derived mesenchymal stemcells none of which is based on materialcells combinations

74 Ongoing clinical trialsWe are aware of six clinical trials (according to wwwclinicaltrialsgov)which have been organized up to date with a TE approach in myocardialrepair In Table 1 we report the five clinical trials according to wwwclinicaltrialsgov In an actively recruiting trial a CorMatrixTM ECM sheet is ap-plied on the epicardium of patients undergoing bypass implantation afteran acute ischaemic event This study was corroborated by a preclinical in-vestigation performed in pigs supporting the cardioprotective and pro-vas-culogenic effect of the matrix In another recently completed trial acombination of allogeneic embryonic stem cell-derived cardiac progenitorcells and fibrin was employed to create an engineered tissue patch thatwas sutured to the necrotic portion of the ventricle cover by a pericardialflap Results of this study in six patients were recently published18 andshowed a promising outcome as to safety (the primary endpoint of thetrial) and hints supporting the concept of functional recovery of the heartIn a different approach therapeutic material (a myocardium specific ECMmatrix) is delivered inside the myocardium using a minimally invasive pro-cedure In this case the choice of the regions of the myocardium to betreated is guided by the mapping of myocardial viability available by elec-tric voltage mapping (eg NOGA system) The clinical trial approved inJapan and previously mentioned (see Section 43) is registered in theJapanese clinical trial registry It will for the first time test human iPSC-derived cardiomyocytes implanted epicardially as cell sheets in patientswith HF As such it is a follow-up study to the completed skeletal myo-blast cell sheet trial by the same group of investigators93 The propensityfor arrhythmia induction and tumour formation as well as immuneresponses to the allograft will have to be monitored carefully Followingthe fast track developmental strategy of the Japanese government thestudy is planned to be performed in three patients under a conditional ap-proval of the cardiomyocyte cell sheet for application in HF repair94

8 Recommendations

bull The application of non-myocytes appears to be safe in patients withIHD and HF but so far largely ineffective Low cell retention at thesite of injury and false expectations as to the outcome of the mostly

small clinical trials which were naturally designed to test for safetyand feasibility but often misinterpreted as efficacy trials contributedto the perception of futile outcome These underpowered trials weresuccessful in all cases but not designed with sufficient power to testefficacy Sufficiently long retention of the biologically active constitu-ent ie either cardiomyocytes or cells with paracrine activity must beensured to render tissue-engineered products effective in the remus-cularizationregeneration of the failing heart

bull TE strategies should be further explored and optimized as they offermeans to significantly enhance cell retention at the site of injury

bull Advanced preclinical development including manufacturing of tissue-engineered products should be in close interaction with the relevantregulatory authorities to be in-line with regulatory demands In addi-tion to an agreement on the GMP-manufacturing process this alsoincludes a detailed discussion of typically rodent and large animalexperiments

bull Further refinement of TE strategies including the testing of three-dimensional printing are attractive to optimize the biological activityof tissue-engineered products ie either contractile performance orsecretome activity or both to continuously develop the next genera-tion tissue-engineered products as well as strategies for their optimaladministration

FundingJPGS was supported by Horizon2020 ERC-2016-COG EVICARE (725229)and H2020 Technobeat (668724) PF was supported by the HungarianNational Research Development and Innovation Office (OTKA KH_17125570 NVKP 16-1-2016-0017 National Heart Program and VEKOP-232-16-2016-00002) and by the Higher Education Institutional ExcellenceProgramme of the Ministry of Human Capacities in Hungary within theframework of the Therapeutic Development thematic programme of theSemmelweis University TE is supported by the DZHK (German Centre forCardiovascular Research) the European Research Council (ERC-AGIndivuHeart) the German Research Foundation (WE 56203-1) and theBritish Heart Foundation (Regenerative Medicine Centres) DJH was sup-ported by the British Heart Foundation (FS1003928270) the NationalInstitute for Health Research University College London HospitalsBiomedical Research Centre Duke-National University Singapore MedicalSchool Singapore Ministry of Healthrsquos National Medical Research Councilunder its Clinician Scientist-Senior Investigator scheme (NMRCCSA-SI00112017) and Collaborative Centre Grant scheme (NMRCCGAug16C006) the Singapore Ministry of Education Academic ResearchFund Tier 2 (MOE2016-T2-2-021) and the COST European Cooperation inScience and Technology) Action EU-CARDIOPROTECTION CA16225CP was supported by Ministero dellrsquoIstruzione Universita e RicercaScientifica (2015583WMX grant) and by Federico II University (Unina) and

Table 1 Ongoing human clinical trials for cardiac tissue engineering

Clinical trial name Materialcellstissue Trial identifier

wwwclinicaltrialsgov

Phase (enrolled

patients)mdash

(publication)

Epicardial infarct repair using CorMatrixVR -ECM

clinical feasibility study (EIR)

CorMatrix-extracellular matrix NCT02887768 Phase 1119

Transplantation of human embryonic stem cell-derived

progenitors in severe heart failure (ESCORT)

Human ESC-derived progenitors

embedded into a fibrin patch

NCT02057900 Phase 157116

A study of VentriGel in post-MI patients VentriGel extracellular matrix hydrogel NCT02305602 Phase 1 (recruiting)

Myocardial assistance by grafting a new bioartificial

upgraded myocardium (MAGNUM trial)

Collagen matrix seeded with bone marrow cells NCT01429415 Completed140

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Compagnia di San Paolo (Programma STAR) MP was supported byMinistero della Salute (RF-2011-02346867) and by Institutional grants(Ricerca Corrente 5 per 1000) JSH was supported by Era-CVD (ANR-16-ECVD-0011-03 Clarify project) and Fondation Leducq (13CVD01CardioStemNet project) WHZ is supported by the DZHK (GermanCenter for Cardiovascular Research) the German Research Foundation(DFG SFB 937 TP18 SFB 1002 TPs C04 S01 IRTG 1618 RP12) and theFoundation Leducq FBE is funded by the DeutscheForschungsgemeinschaft (DFG German Research Foundation) ndashProjektnummer 326998133 ndash TRR 225 (subproject C01 to FBE) and EN45311-1 SMD is supported by the British Heart Foundation [PG168532471 and PG184433790] and the National Institute for Health ResearchUniversity College London Hospitals Biomedical Research Centre

Conflict of interest PF is founder and CEO of Pharmahungary a group ofRampD companies WHZ is founder and scientific advisor of RepaironGmbH

References1 Iismaa SE Kaidonis X Nicks AM Bogush N Kikuchi K Naqvi N Harvey RP Husain

A Graham RM Comparative regenerative mechanisms across different mammaliantissues NPJ Regen Med 201836

2 A futile cycle in cell therapy Nat Biotechnol 2017352913 Madonna R Van Laake LW Davidson SM Engel FB Hausenloy DJ Lecour S Leor J

Perrino C Schulz R Ytrehus K Landmesser U Mummery CL Janssens S WillersonJ Eschenhagen T Ferdinandy P Sluijter JPG Position paper of the European Societyof Cardiology Working Group Cellular Biology of the Heart cell-based therapiesfor myocardial repair and regeneration in ischemic heart disease and heart failureEur Heart J 2016371789ndash1798

4 Fernandez-Aviles F Sanz-Ruiz R Climent AM Badimon L Bolli R Charron DFuster V Janssens S Kastrup J Kim HS Luscher TF Martin JF Menasche P SimariRD Stone GW Terzic A Willerson JT Wu JC TACTICS (Transnational Alliancefor Regenerative Therapies in Cardiovascular Syndromes) Writing Group AuthorsTask Force Members Chairpersons Basic Research Subcommittee TranslationalResearch Subcommittee Challenges of Cardiovascular Regenerative MedicineSubcommittee Tissue Engineering Subcommittee Delivery Navigation Trackingand Assessment Subcommittee Clinical Trials Subcommittee Regulatory and fund-ing strategies subcommittee Delivery Navigation Tracking and AssessmentSubcommittee Global position paper on cardiovascular regenerative medicine EurHeart J 2017382532ndash2546

5 Eschenhagen T Bolli R Braun T Field LJ Fleischmann BK Frisen J Giacca M HareJM Houser S Lee RT Marban E Martin JF Molkentin JD Murry CE Riley PR Ruiz-Lozano P Sadek HA Sussman MA Hill JA Cardiomyocyte regeneration a consen-sus statement Circulation 2017136680ndash686

6 Nguyen P Neofytou E Rhee J Wu J Potential strategies to address the major clini-cal barriers facing stem cell regenerative therapy for cardiovascular disease a re-view JAMA Cardiol 20161953ndash962

7 Hou D Youssef EA-S Brinton TJ Zhang P Rogers P Price ET Yeung ACJohnstone BH Yock PG March KL Radiolabeled cell distribution after intramyocar-dial intracoronary and interstitial retrograde coronary venous delivery implicationsfor current clinical trials Circulation 2005112I150ndashI156

8 van den Akker F Feyen DAM van den Hoogen P van Laake LW van Eeuwijk ECMHoefer I Pasterkamp G Chamuleau SAJ Grundeman PF Doevendans PA Sluijter JPGIntramyocardial stem cell injection go(ne) with the flow Eur Heart J 201738184ndash186

9 Feyen DAM Gaetani R Deddens J van Keulen D van Opbergen C Poldervaart MAlblas J Chamuleau S van Laake LW Doevendans PA Sluijter JPG Gelatin micro-spheres as vehicle for cardiac progenitor cells delivery to the myocardium AdvHealthc Mater 201651071ndash1079

10 Gaetani R Feyen DAM Verhage V Slaats R Messina E Christman KL GiacomelloA Doevendans PAFM Sluijter JPG Epicardial application of cardiac progenitor cellsin a 3D-printed gelatinhyaluronic acid patch preserves cardiac function after myo-cardial infarction Biomaterials 201561339ndash348

11 Pintus E Baldassarri M Perazzo L Natali S Ghinelli D Buda R Stem cells in osteo-chondral tissue engineering Adv Exp Med Biol 20181058359ndash372

12 Rubart M Pasumarthi K Nakajima H Soonpaa M Nakajima H Field L Physiologicalcoupling of donor and host cardiomyocytes after cellular transplantation Circ Res2003921217ndash1224

13 Didie M Christalla P Rubart M Muppala V Doker S Unsold B El-Armouche ARau T Eschenhagen T Schwoerer AP Ehmke H Schumacher U Fuchs S Lange CBecker A Tao W Scherschel JA Soonpaa MH Yang T Lin Q Zenke M Han D-WScholer HR Rudolph C Steinemann D Schlegelberger B Kattman S Witty AKeller G Field LJ Zimmermann W-H Parthenogenetic stem cells for tissue-engineered heart repair J Clin Invest 20131231285ndash1298

14 Zimmermann W-H Melnychenko I Wasmeier G Didie M Naito H Nixdorff UHess A Budinsky L Brune K Michaelis B Dhein S Schwoerer A Ehmke HEschenhagen T Engineered heart tissue grafts improve systolic and diastolic func-tion in infarcted rat hearts Nat Med 200612452ndash458

15 Shiba Y Fernandes S Zhu W-Z Filice D Muskheli V Kim J Palpant NJ Gantz JMoyes KW Reinecke H Van Biber B Dardas T Mignone JL Izawa A Hanna RViswanathan M Gold JD Kotlikoff MI Sarvazyan N Kay MW Murry CE LaflammeMA Human ES-cell-derived cardiomyocytes electrically couple and suppressarrhythmias in injured hearts Nature 2012489322ndash325

16 Chong JJH Yang X Don CW Minami E Liu Y-W Weyers JJ Mahoney WM VanBiber B Cook SM Palpant NJ Gantz JA Fugate JA Muskheli V Gough GM VogelKW Astley CA Hotchkiss CE Baldessari A Pabon L Reinecke H Gill EA NelsonV Kiem H-P Laflamme MA Murry CE Human embryonic-stem-cell-derived cardio-myocytes regenerate non-human primate hearts Nature 2014510273ndash277

17 Liu B Shi R Li X Liu Y Feng X Chen X Fan X Zhang Y Zhang W Tang J ZhouX Li N Lu X Xu Z Downregulation of L-type voltage-gated Ca2thorn voltage-gatedKthorn and large-conductance Ca2thorn-activated Kthorn channels in vascular myocytes fromsalt-loading offspring rats exposed to prenatal hypoxia J Am Heart Assoc 20187piie008148

18 Menasche P Vanneaux V Hagege A Bel A Cholley B Parouchev A Cacciapuoti IAl-Daccak R Benhamouda N Blons H Agbulut O Tosca L Trouvin J-HFabreguettes J-R Bellamy V Charron D Tartour E Tachdjian G Desnos MLarghero J Transplantation of human embryonic stem cell-derived cardiovascularprogenitors for severe ischemic left ventricular dysfunction J Am Coll Cardiol 201871429ndash438

19 Riegler J Tiburcy M Ebert A Tzatzalos E Raaz U Abilez OJ Shen Q KooremanNG Neofytou E Chen VC Wang M Meyer T Tsao PS Connolly AJ Couture LAGold JD Zimmermann WH Wu JC Human engineered heart muscles engraft andsurvive long term in a rodent myocardial infarction model Circ Res 2015117720ndash730

20 Qin X Riegler J Tiburcy M Zhao X Chour T Ndoye B Nguyen M Adams JAmeen M Denney TS Jr Yang PC Nguyen P Zimmermann WH Wu JC Magneticresonance imaging of cardiac strain pattern following transplantation of human tis-sue engineered heart muscles Circ Cardiovasc Imaging 20169piie004731

21 Tiburcy M Hudson JE Balfanz P Schlick S Meyer T Chang Liao M-L Levent ERaad F Zeidler S Wingender E Riegler J Wang M Gold JD Kehat I Wettwer ERavens U Dierickx P van Laake LW Goumans MJ Khadjeh S Toischer KHasenfuss G Couture LA Unger A Linke WA Araki T Neel B Keller G GepsteinL Wu JC Zimmermann W-H Defined engineered human myocardium with ad-vanced maturation for applications in heart failure modeling and repair Circulation20171351832ndash1847

22 Weinberger F Breckwoldt K Pecha S Kelly A Geertz B Starbatty J Yorgan TCheng K-H Lessmann K Stolen T Scherrer-Crosbie M Smith G ReichenspurnerH Hansen A Eschenhagen T Cardiac repair in guinea pigs with human engineeredheart tissue from induced pluripotent stem cells Sci Transl Med 20168363ra148

23 Gerbin KA Yang X Murry CE Coulombe KL Enhanced electrical integration ofengineered human myocardium via intramyocardial versus epicardial delivery in in-farcted rat hearts PLoS One 201510e0131446

24 Shadrin IY Allen BW Qian Y Jackman CP Carlson AL Juhas ME Bursac NCardiopatch platform enables maturation and scale-up of human pluripotent stemcell-derived engineered heart tissues Nat Commun 201781825

25 Ulmer BM Stoehr A Schulze ML Patel S Gucek M Mannhardt I Funcke S MurphyE Eschenhagen T Hansen A Contractile work contributes to maturation of energymetabolism in hiPSC-derived cardiomyocytes Stem Cell Reports 201810834ndash847

26 Abilez OJ Tzatzalos E Yang H Zhao M-T Jung G Zollner AM Tiburcy M Riegler JMatsa E Shukla P Zhuge Y Chour T Chen VC Burridge PW Karakikes I Kuhl EBernstein D Couture LA Gold JD Zimmermann WH Wu JC Passive stretch indu-ces structural and functional maturation of engineered heart muscle as predicted bycomputational modeling Stem Cells 201836265ndash277

27 Ruan J-L Tulloch NL Razumova MV Saiget M Muskheli V Pabon L Reinecke HRegnier M Murry CE Mechanical stress conditioning and electrical stimulation pro-mote contractility and force maturation of induced pluripotent stem cell-derivedhuman cardiac tissue Circulation 20161341557ndash1567

28 Kana K Song H Laschinger C Zandstra PW Radisic M PI3K phosphorylation islinked to improved electrical excitability in an in vitro engineered heart tissue diseasemodel system Tissue Eng Part A 2015212379ndash2389

29 Godier-Furnemont AF Tiburcy M Wagner E Dewenter M Lammle S El-Armouche A Lehnart SE Vunjak-Novakovic G Zimmermann WH Physiologicforce-frequency response in engineered heart muscle by electromechanical stimula-tion Biomaterials 20156082ndash91

30 Maidhof R Tandon N Lee EJ Luo J Duan Y Yeager K Konofagou E Vunjak-NovakovicG Biomimetic perfusion and electrical stimulation applied in concert improved the as-sembly of engineered cardiac tissue J Tissue Eng Regen Med 20126e12ndashe23

31 Zhang D Shadrin IY Lam J Xian HQ Snodgrass HR Bursac N Tissue-engineeredcardiac patch for advanced functional maturation of human ESC-derived cardiomyo-cytes Biomaterials 2013345813ndash5820

32 Yang X Pabon L Murry CE Engineering adolescence maturation of human pluripo-tent stem cell-derived cardiomyocytes Circ Res 2014114511ndash523

Tissue engineering and cell-based therapies for cardiac repair in ischaemic heart disease and heart failure 497D

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ape Town Libraries user on 26 April 2019

33 Ronaldson-Bouchard K Ma SP Yeager K Chen T Song LJ Sirabella D Morikawa K

Teles D Yazawa M Vunjak-Novakovic G Advanced maturation of human cardiactissue grown from pluripotent stem cells Nature 2018556239ndash243

34 Yang X Rodriguez M Pabon L Fischer KA Reinecke H Regnier M Sniadecki NJRuohola-Baker H Murry CE Tri-iodo-l-thyronine promotes the maturation of hu-man cardiomyocytes-derived from induced pluripotent stem cells J Mol Cell Cardiol201472296ndash304

35 Hirt MN Boeddinghaus J Mitchell A Schaaf S Bornchen C Muller C Schulz HHubner N Stenzig J Stoehr A Neuber C Eder A Luther PK Hansen AEschenhagen T Functional improvement and maturation of rat and human engi-neered heart tissue by chronic electrical stimulation J Mol Cell Cardiol 201474151ndash161

36 Nunes SS Miklas JW Liu J Aschar-Sobbi R Xiao Y Zhang B Jiang J Masse SGagliardi M Hsieh A Thavandiran N Laflamme MA Nanthakumar K Gross GJBackx PH Keller G Radisic M Biowire a platform for maturation of human pluripo-tent stem cell-derived cardiomyocytes Nat Methods 201310781ndash787

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38 Liaw NY Zimmermann WH Mechanical stimulation in the engineering of heartmuscle Adv Drug Deliv Rev 201696156ndash160

39 Schaaf S Shibamiya A Mewe M Eder A Stohr A Hirt MN Rau T ZimmermannW-H Conradi L Eschenhagen T Hansen A Human engineered heart tissue as aversatile tool in basic research and preclinical toxicology PLoS One 20116e26397

40 Kensah G Roa Lara A Dahlmann J Zweigerdt R Schwanke K Hegermann J SkvorcD Gawol A Azizian A Wagner S Maier LS Krause A Drager G Ochs M HaverichA Gruh I Martin U Murine and human pluripotent stem cell-derived cardiac bodiesform contractile myocardial tissue in vitro Eur Heart J 2013341134ndash1146

41 Pedrotty DM Klinger RY Kirkton RD Bursac N Cardiac fibroblast paracrine fac-tors alter impulse conduction and ion channel expression of neonatal rat cardio-myocytes Cardiovasc Res 200983688ndash697

42 Naito H Melnychenko I Didie M Schneiderbanger K Schubert P Rosenkranz SEschenhagen T Zimmermann WH Optimizing engineered heart tissue for thera-peutic applications as surrogate heart muscle Circulation 2006114I72ndashI78

43 Detert S Stamm C Beez C Diedrichs F Ringe J Van Linthout S Seifert M TschopeC Sittinger M Haag M The atrial appendage as a suitable source to generatecardiac-derived adherent proliferating cells for regenerative cell-based therapiesJ Tissue Eng Regen Med 201812e1404ndashe1e17

44 Devalla HD Schwach V Ford JW Milnes JT El-Haou S Jackson C Gkatzis K ElliottDA Chuva de Sousa Lopes SM Mummery CL Verkerk AO Passier R Atrial-likecardiomyocytes from human pluripotent stem cells are a robust preclinical modelfor assessing atrial-selective pharmacology EMBO Mol Med 20157394ndash410

45 Witty AD Mihic A Tam RY Fisher SA Mikryukov A Shoichet MS Li R-K KattmanSJ Keller G Generation of the epicardial lineage from human pluripotent stem cellsNat Biotechnol 2014321026ndash1035

46 Guadix JA Orlova VV Giacomelli E Bellin M Ribeiro MC Mummery CL Perez-Pomares JM Passier R Human pluripotent stem cell differentiation into functionalepicardial progenitor cells Stem Cell Reports 201791754ndash1764

47 Protze SI Liu J Nussinovitch U Ohana L Backx PH Gepstein L Keller GMSinoatrial node cardiomyocytes derived from human pluripotent cells function as abiological pacemaker Nat Biotechnol 20163556ndash68

48 Cyganek L Tiburcy M Sekeres K Gerstenberg K Bohnenberger H Lenz C HenzeS Stauske M Salinas G Zimmermann WH Hasenfuss G Guan K Deep phenotyp-ing of human induced pluripotent stem cell-derived atrial and ventricular cardio-myocytes JCI Insight 20183pii99941

49 Tulloch NL Muskheli V Razumova MV Korte FS Regnier M Hauch KD Pabon LReinecke H Murry CE Growth of engineered human myocardium with mechanicalloading and vascular coculture Circ Res 201110947ndash59

50 Gao L Gregorich ZR Zhu W Mattapally S Oduk Y Lou X Kannappan RBorovjagin AV Walcott GP Pollard AE Fast VG Hu X Lloyd SG Ge Y Zhang JLarge cardiac muscle patches engineered from human induced-pluripotent stemcell-derived cardiac cells improve recovery from myocardial infarction in swineCirculation 20181371712ndash1730

51 Segers VFM Brutsaert DL De Keulenaer GW Cardiac remodeling endothelial cellshave more to say than just no Front Physiol 20189382

52 Li Y Asfour H Bursac N Age-dependent functional crosstalk between cardiacfibroblasts and cardiomyocytes in a 3D engineered cardiac tissue Acta Biomater201755120ndash130

53 Makkar RR Smith RR Cheng K Malliaras K Thomson LEJ Berman D Czer LSCMarban L Mendizabal A Johnston PV Russell SD Schuleri KH Lardo ACGerstenblith G Marban E Intracoronary cardiosphere-derived cells for heart regen-eration after myocardial infarction (CADUCEUS) a prospective randomised phase1 trial Lancet 2012379895ndash904

54 Bartunek J Behfar A Dolatabadi D Vanderheyden M Ostojic M Dens J El NakadiB Banovic M Beleslin B Vrolix M Legrand V Vrints C Vanoverschelde JL Crespo-Diaz R Homsy C Tendera M Waldman S Wijns W Terzic A Cardiopoietic stemcell therapy in heart failure the C-CURE (Cardiopoietic stem Cell therapy in heartfailURE) multicenter randomized trial with lineage-specified biologics J Am CollCardiol 2013612329ndash2338

55 Menasche P Cell therapy trials for heart regenerationmdashlessons learned and futuredirections Nat Rev Cardiol 201815659ndash671

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57 Crespo-Diaz R Yamada S Bartunek J Perez-Terzic C de Waele P Mauen S TerzicA Behfar A Cardiopoietic index predicts heart repair fitness of patient-derivedstem cells Biomarkers Med 20159639ndash649

58 Dimmeler S Leri A Aging and disease as modifiers of efficacy of cell therapy CircRes 20081021319ndash1330

59 Felix NJ Allen PM Specificity of T-cell alloreactivity Nat Rev Immunol 20077942ndash953

60 Braza MS van Leent MMT Lameijer M Sanchez-Gaytan BL Arts RJW Perez-Medina C Conde P Garcia MR Gonzalez-Perez M Brahmachary M Fay F Kluza EKossatz S Dress RJ Salem F Rialdi A Reiner T Boros P Strijkers GJ Calcagno CCGinhoux F Marazzi I Lutgens E Nicolaes GAF Weber C Swirski FK NahrendorfM Fisher EA Duivenvoorden R Fayad ZA Netea MG Mulder WJM Ochando JInhibiting inflammation with myeloid cell-specific nanobiologics promotes organtransplant acceptance Immunity 201849819ndash828e6

61 Gornalusse GG Hirata RK Funk SE Riolobos L Lopes VS Manske G Prunkard DColunga AG Hanafi L-A Clegg DO Turtle C Russell DW HLA-E-expressing plu-ripotent stem cells escape allogeneic responses and lysis by NK cells Nat Biotechnol201735765ndash772

62 Di Stasi A Tey S-K Dotti G Fujita Y Kennedy-Nasser A Martinez C Straathof KLiu E Durett AG Grilley B Liu H Cruz CR Savoldo B Gee AP Schindler J KranceRA Heslop HE Spencer DM Rooney CM Brenner MK Inducible apoptosis as asafety switch for adoptive cell therapy N Engl J Med 20113651673ndash1683

63 Jansen Of Lorkeers SJ Eding JEC Vesterinen HM van der Spoel TIG Sena ESDuckers HJ Doevendans PA Macleod MR Chamuleau SAJ Similar effect of autolo-gous and allogeneic cell therapy for ischemic heart disease systematic review andmeta-analysis of large animal studies Circ Res 201511680ndash86

64 Beck J Oellerich M Schulz U Schauerte V Reinhard L Fuchs U Knabbe CZittermann A Olbricht C Gummert JF Shipkova M Birschmann I Wieland ESchutz E Donor-derived cell-free DNA is a novel universal biomarker for allograftrejection in solid organ transplantation Transplant Proc 2015472400ndash2403

65 Malliaras K Li T-S Luthringer D Terrovitis J Cheng K Chakravarty T Galang GZhang Y Schoenhoff F Van Eyk J Marban L Marban E Safety and efficacy of alloge-neic cell therapy in infarcted rats transplanted with mismatched cardiosphere-derived cells Circulation 2012125100ndash112

66 Kawamura T Miyagawa S Fukushima S Maeda A Kashiyama N Kawamura A MikiK Okita K Yoshida Y Shiina T Ogasawara K Miyagawa S Toda K Okuyama HSawa Y Cardiomyocytes derived from MHC-homozygous induced pluripotent stemcells exhibit reduced allogeneic immunogenicity in MHC-matched non-human pri-mates Stem Cell Reports 20166312ndash320

67 Taylor CJ Peacock S Chaudhry AN Bradley JA Bolton EM Generating an iPSCbank for HLA-matched tissue transplantation based on known donor and recipientHLA types Cell Stem Cell 201211147ndash152

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74 Zimmermann W-H Schneiderbanger K Schubert P Didie M Munzel F Heubach JFKostin S Neuhuber WL Eschenhagen T Tissue engineering of a differentiated car-diac muscle construct Circ Res 200290223ndash230

75 Hansen A Eder A Bonstrup M Flato M Mewe M Schaaf S Aksehirlioglu BSchwoerer AP Schworer A Uebeler J Eschenhagen T Development of adrug screening platform based on engineered heart tissue Circ Res 201010735ndash44

76 Zimmermann WH Fink C Kralisch D Remmers U Weil J Eschenhagen T Three-dimensional engineered heart tissue from neonatal rat cardiac myocytes BiotechnolBioeng 200068106ndash114

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498 R Madonna et alD

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cardiovascresarticle-abstract11534885292411 by University of C

ape Town Libraries user on 26 April 2019

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electrical-conduction function in rats with myocardial infarction Life Sci 201411834ndash38

80 Yanamandala M Zhu W Garry DJ Kamp TJ Hare JM Jun H-W Yoon Y-S BursacN Prabhu SD Dorn GW Bolli R Kitsis RN Zhang J Overcoming the roadblocksto cardiac cell therapy using tissue engineering J Am Coll Cardiol 201770766ndash775

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84 Shin SR Jung SM Zalabany M Kim K Zorlutuna P Kim S B Nikkhah M Khabiry MAzize M Kong J Wan K-T Palacios T Dokmeci MR Bae H Tang X(S)Khademhosseini A Carbon-nanotube-embedded hydrogel sheets for engineeringcardiac constructs and bioactuators ACS Nano 201372369ndash2380

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87 Tiburcy M Didie M Boy O Christalla P Doker S Naito H Karikkineth BC El-Armouche A Grimm M Nose M Eschenhagen T Zieseniss A Katschinksi DMHamdani N Linke WA Yin X Mayr M Zimmermann W-H Terminal differentia-tion advanced organotypic maturation and modeling of hypertrophic growth inengineered heart tissue Circ Res 20111091105ndash1114

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89 Yang J Yamato M Nishida K Ohki T Kanzaki M Sekine H Shimizu T Okano TCell delivery in regenerative medicine the cell sheet engineering approach J ControlRelease 2006116193ndash203

90 Miyahara Y Nagaya N Kataoka M Yanagawa B Tanaka K Hao H Ishino K IshidaH Shimizu T Kangawa K Sano S Okano T Kitamura S Mori H Monolayered mes-enchymal stem cells repair scarred myocardium after myocardial infarction NatMed 200612459ndash465

91 Narita T Shintani Y Ikebe C Kaneko M Campbell NG Coppen SR Uppal R SawaY Yashiro K Suzuki K The use of scaffold-free cell sheet technique to refine mes-enchymal stromal cell-based therapy for heart failure Mol Ther 201321860ndash867

92 Masumoto H Matsuo T Yamamizu K Uosaki H Narazaki G Katayama S Marui AShimizu T Ikeda T Okano T Sakata R Yamashita JK Pluripotent stem cell-engineered cell sheets reassembled with defined cardiovascular populations amelio-rate reduction in infarct heart function through cardiomyocyte-mediated neovascu-larization Stem Cells 2012301196ndash1205

93 Sawa Y Yoshikawa Y Toda K Fukushima S Yamazaki K Ono M Sakata YHagiwara N Kinugawa K Miyagawa S Safety and efficacy of autologous skeletalmyoblast sheets (TCD-51073) for the treatment of severe chronic heart failure dueto ischemic heart disease Circ J 201579991ndash999

94 Cyranoski D lsquoReprogrammedrsquo stem cells approved to mend human hearts for thefirst time Nature 2018557619ndash620

95 Shimizu T Yamato M Isoi Y Akutsu T Setomaru T Abe K Kikuchi A Umezu MOkano T Fabrication of pulsatile cardiac tissue grafts using a novel 3-dimensionalcell sheet manipulation technique and temperature-responsive cell culture surfacesCirc Res 200290e40

96 Groll J Boland T Blunk T Burdick JA Cho D-W Dalton PD Derby B Forgacs GLi Q Mironov VA Moroni L Nakamura M Shu W Takeuchi S Vozzi G WoodfieldTBF Xu T Yoo JJ Malda J Biofabrication reappraising the definition of an evolvingfield Biofabrication 20168013001

97 Cui H Miao S Esworthy T Zhou X Lee SJ Liu C Yu ZX Fisher JP Mohiuddin MZhang LG 3D bioprinting for cardiovascular regeneration and pharmacology AdvDrug Deliv Rev 2018132252ndash269

98 Bejleri D Streeter BW Nachlas ALY Brown ME Gaetani R Christman KL DavisME A bioprinted cardiac patch composed of cardiac-specific extracellular matrixand progenitor cells for heart repair Adv Healthc Mater 201871800672

99 Ionov L 4D biofabrication materials methods and applications Adv Healthc Mater201871800412

100 Schaefer JA Guzman PA Riemenschneider SB Kamp TJ Tranquillo RT A cardiacpatch from aligned microvessel and cardiomyocyte patches J Tissue Eng Regen Med201812546ndash556

101 Jackman CP Ganapathi AM Asfour H Qian Y Allen BW Li Y Bursac NEngineered cardiac tissue patch maintains structural and electrical properties afterepicardial implantation Biomaterials 201815948ndash58

102 Dvir T Timko BP Brigham MD Naik SR Karajanagi SS Levy O Jin H Parker KKLanger R Kohane DS Nanowired three-dimensional cardiac patches NatNanotechnol 20116720ndash725

103 Boothe SD Myers JD Pok S Sun J Xi Y Nieto RM Cheng J Jacot JG The effect ofsubstrate stiffness on cardiomyocyte action potentials Cell Biochem Biophys 201674527ndash535

104 Roeder I Loeffler M Glauche I Other P Towards a quantitative understanding ofstem cell-niche interaction experiments models and technologies Blood Cells MolDis 201146308ndash317

105 Chimenti I Massai D Morbiducci U Beltrami AP Pesce M Messina E Stem cellspheroids and ex vivo niche modeling rationalization and scaling-up J CardiovascTransl Res 201710150ndash166

106 Montgomery M Ahadian S Davenport Huyer L Lo Rito M Civitarese RAVanderlaan RD Wu J Reis LA Momen A Akbari S Pahnke A Li R-K CaldaroneCA Radisic M Flexible shape-memory scaffold for minimally invasive delivery offunctional tissues Nat Mater 2017161038ndash1046

107 Sepantafar M Maheronnaghsh R Mohammadi H Rajabi-Zeleti S Annabi NAghdami N Baharvand H Stem cells and injectable hydrogels synergistic therapeu-tics in myocardial repair Biotechnol Adv 201634362ndash379

108 Madonna R Petrov L Teberino MA Manzoli L Karam J-P Renna FV Ferdinandy PMontero-Menei CN Yla-Herttuala S De Caterina R Transplantation of adipose tis-sue mesenchymal cells conjugated with VEGF-releasing microcarriers promotes re-pair in murine myocardial infarction Cardiovasc Res 201510839ndash49

109 Wang LL Liu Y Chung JJ Wang T Gaffey AC Lu M Cavanaugh CA Zhou SKanade R Atluri P Morrisey EE Burdick JA Local and sustained miRNA deliveryfrom an injectable hydrogel promotes cardiomyocyte proliferation and functionalregeneration after ischemic injury Nat Biomed Eng 20171983ndash992

110 Waters R Alam P Pacelli S Chakravarti AR Ahmed RPH Paul A Stem cell-inspired secretome-rich injectable hydrogel to repair injured cardiac tissue ActaBiomater 20186995ndash106

111 Liu H Paul C Xu M Optimal environmental stiffness for stem cell mediated ische-mic myocardium repair Methods Mol Biol 20171553293ndash304

112 Bao R Tan B Liang S Zhang N Wang W Liu W A pi-pi conjugation-containingsoft and conductive injectable polymer hydrogel highly efficiently rebuilds cardiacfunction after myocardial infarction Biomaterials 201712263ndash71

113 Morez C Noseda M Paiva MA Belian E Schneider MD Stevens MM Enhanced effi-ciency of genetic programming toward cardiomyocyte creation through topographi-cal cues Biomaterials 20157094ndash104

114 Ebrahimi B In vivo reprogramming for heart regeneration a glance at efficiency envi-ronmental impacts challenges and future directions J Mol Cell Cardiol 201710861ndash72

115 Song Y Zhang C Zhang J Sun N Huang K Li H Wang Z Huang K Wang L An in-jectable silk sericin hydrogel promotes cardiac functional recovery after ischemicmyocardial infarction Acta Biomater 201641210ndash223

116 Kim BH Park M Park HJ Lee SH Choi SY Park CG Han SM Heo CY Choy YBProlonged acute suppression of cysteinyl leukotriene to reduce capsular contrac-ture around silicone implants Acta Biomater 201751209ndash219

117 Kimura W Xiao F Canseco DC Muralidhar S Thet S Zhang HM Abderrahman YChen R Garcia JA Shelton JM Richardson JA Ashour AM Asaithamby A Liang HXing C Lu Z Zhang CC Sadek HA Hypoxia fate mapping identifies cycling cardio-myocytes in the adult heart Nature 2015523226ndash230

118 Vishwakarma A Bhise NS Evangelista MB Rouwkema J Dokmeci MRGhaemmaghami AM Vrana NE Khademhosseini A Engineering immunomodulatorybiomaterials to tune the inflammatory response Trends Biotechnol 201634470ndash482

119 Aurora AB Porrello ER Tan W Mahmoud AI Hill JA Bassel-Duby R Sadek HAOlson EN Macrophages are required for neonatal heart regeneration J Clin Invest20141241382ndash1392

120 Hernandez MJ Christman KL Designing acellular injectable biomaterial therapeuticsfor treating myocardial infarction and peripheral artery disease JACC Basic Transl Sci20172212ndash226

121 Mann DL Lee RJ Coats AJS Neagoe G Dragomir D Pusineri E Piredda M BettariL Kirwan B-A Dowling R Volterrani M Solomon SD Sabbah HN Hinson AAnker SD One-year follow-up results from AUGMENT-HF a multicentre random-ized controlled clinical trial of the efficacy of left ventricular augmentation withAlgisyl in the treatment of heart failure Eur J Heart Fail 201618314ndash325

122 Anker SD Coats AJS Cristian G Dragomir D Pusineri E Piredda M Bettari LDowling R Volterrani M Kirwan B-A Filippatos G Mas J-L Danchin N SolomonSD Lee RJ Ahmann F Hinson A Sabbah HN Mann DL A prospective comparisonof alginate-hydrogel with standard medical therapy to determine impact on func-tional capacity and clinical outcomes in patients with advanced heart failure(AUGMENT-HF trial) Eur Heart J 2015362297ndash2309

123 Frey N Linke A Suselbeck T Muller-Ehmsen J Vermeersch P Schoors DRosenberg M Bea F Tuvia S Leor J Intracoronary delivery of injectable bioabsorb-able scaffold (IK-5001) to treat left ventricular remodeling after ST-elevation myo-cardial infarction a first-in-man study Circ Cardiovasc Interv 20147806ndash812

Tissue engineering and cell-based therapies for cardiac repair in ischaemic heart disease and heart failure 499D

ownloaded from

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cardiovascresarticle-abstract11534885292411 by University of C

ape Town Libraries user on 26 April 2019

124 Wei K Serpooshan V Hurtado C Diez-Cu~nado M Zhao M Maruyama S Zhu W

Fajardo G Noseda M Nakamura K Tian X Liu Q Wang A Matsuura Y BushwayP Cai W Savchenko A Mahmoudi M Schneider MD van den Hoff MJB Butte MJYang PC Walsh K Zhou B Bernstein D Mercola M Ruiz-Lozano P EpicardialFSTL1 reconstitution regenerates the adult mammalian heart Nature 2015525479ndash485

125 Sluijter JPG Davidson SM Boulanger CM Buzas EI de Kleijn DPV Engel FB GiriczZ Hausenloy DJ Kishore R Lecour S Leor J Madonna R Perrino C Prunier FSahoo S Schiffelers RM Schulz R Van Laake LW Ytrehus K Ferdinandy PExtracellular vesicles in diagnostics and therapy of the ischaemic heart positionPaper from the Working Group on Cellular Biology of the Heart of the EuropeanSociety of Cardiology Cardiovasc Res 201811419ndash34

126 Barile L Cervio E Lionetti V Milano G Ciullo A Biemmi V Bolis S Altomare CMatteucci M Di Silvestre D Brambilla F Fertig TE Torre T Demertzis S Mauri PMoccetti T Vassalli G Cardioprotection by cardiac progenitor cell-secreted exo-somes role of pregnancy-associated plasma protein-A Cardiovasc Res 2018114992ndash1005

127 El Harane N Kervadec A Bellamy V Pidial L Neametalla HJ Perier MC LimaCorrea B Thiebault L Cagnard N Duche A Brunaud C Lemitre M Gauthier JBourdillon AT Renault MP Hovhannisyan Y Paiva S Colas AR Agbulut O HagegeA Silvestre JS Menasche P Renault NKE Acellular therapeutic approach for heartfailure in vitro production of extracellular vesicles from human cardiovascular pro-genitors Eur Heart J 2018391835ndash1847

128 Chen CW Wang LL Zaman S Gordon J Arisi MF Venkataraman CM Chung JJHung G Gaffey AC Spruce LA Fazelinia H Gorman RC Seeholzer SH Burdick JAAtluri P Sustained release of endothelial progenitor cell-derived extracellularvesicles from shear-thinning hydrogels improves angiogenesis and promotes func-tion after myocardial infarction Cardiovasc Res 20181141029ndash1040

129 Pape AC Bakker MH Tseng CC Bastings MM Koudstaal S Agostoni P ChamuleauSA Dankers PY An injectable and drug-loaded supramolecular hydrogel for localcatheter injection into the pig heart J Vis Exp 2015e52450

130 Koudstaal S Bastings MMC Feyen DAM Waring CD van Slochteren FJ DankersPYW Torella D Sluijter JPG Nadal-Ginard B Doevendans PA Ellison GMChamuleau SAJ Sustained delivery of insulin-like growth factor-1hepatocytegrowth factor stimulates endogenous cardiac repair in the chronic infarcted pigheart J Cardiovasc Transl Res 20147232ndash241

131 Hastings CL Roche ET Ruiz-Hernandez E Schenke-Layland K Walsh CJ DuffyGP Drug and cell delivery for cardiac regeneration Adv Drug Deliv Rev 20158485ndash106

132 Gathier WA van Ginkel DJ van der Naald M van Slochteren FJ Doevendans PAChamuleau SAJ Retrograde coronary venous infusion as a delivery strategy in re-generative cardiac therapy an overview of preclinical and clinical data J CardiovascTransl Res 201811173ndash181

133 Tang XL Nakamura S Li Q Wysoczynski M Gumpert AM Wu WJ Hunt GStowers H Ou Q Bolli R Repeated administrations of cardiac progenitor cells aresuperior to a single administration of an equivalent cumulative dose J Am HeartAssoc 20187piie007400

134 Chaudhuri R Ramachandran M Moharil P Harumalani M Jaiswal AK Biomaterialsand cells for cardiac tissue engineering current choices Mater Sci Eng C Mater BiolAppl 201779950ndash957

135 Bel A Planat-Bernard V Saito A Bonnevie L Bellamy V Sabbah L Bellabas LBrinon B Vanneaux V Pradeau P Peyrard S Larghero J Pouly J Binder P Garcia SShimizu T Sawa Y Okano T Bruneval P Desnos M Hagege AA Casteilla L PuceatM Menasche P Composite cell sheets a further step toward safe and effectivemyocardial regeneration by cardiac progenitors derived from embryonic stem cellsCirculation 2010122S118ndashS123

136 Kawatou M Masumoto H Fukushima H Morinaga G Sakata R Ashihara TYamashita JK Modelling Torsade de Pointes arrhythmias in vitro in 3D human iPScell-engineered heart tissue Nat Commun 201781078

137 Qi C Yan X Huang C Melerzanov A Du Y Biomaterials as carrier barrier and re-actor for cell-based regenerative medicine Protein Cell 20156638ndash653

138 Kempf H Kropp C Olmer R Martin U Zweigerdt R Cardiac differentiation of humanpluripotent stem cells in scalable suspension culture Nat Protoc 2015101345ndash1361

139 Rojas SV Kensah G Rotaermel A Baraki H Kutschka I Zweigerdt R Martin UHaverich A Gruh I Martens A Transplantation of purified iPSC-derived cardiomyo-cytes in myocardial infarction PLoS One 201712e0173222

140 Chachques JC Trainini JC Lago N Cortes-Morichetti M Schussler O CarpentierA Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium(MAGNUM trial) clinical feasibility study Ann Thorac Surg 200885901ndash908

141 Ferdinandy P Hausenloy DJ Heusch G Baxter GF Schulz R Interaction of risk fac-tors comorbidities and comedications with ischemiareperfusion injury and cardio-protection by preconditioning postconditioning and remote conditioningPharmacol Rev 2014661142ndash1174

142 Hausenloy DJ Garcia-Dorado D Boslashtker HE Davidson SM Downey J Engel FBJennings R Lecour S Leor J Madonna R Ovize M Perrino C Prunier F Schulz RSluijter JPG Van Laake LW Vinten-Johansen J Yellon DM Ytrehus K Heusch GFerdinandy P Novel targets and future strategies for acute cardioprotection posi-tion Paper of the European Society of Cardiology Working Group on CellularBiology of the Heart Cardiovasc Res 2017113564ndash585

143 Corbett MS Webster A Hawkins R Woolacott N Innovative regenerative medi-cines in the EU a better future in evidence BMC Med 20171549

144 Menasche P Hagege AA Vilquin J-T Desnos M Abergel E Pouzet B Bel ASarateanu S Scorsin M Schwartz K Bruneval P Benbunan M Marolleau J-P DubocD Autologous skeletal myoblast transplantation for severe postinfarction left ven-tricular dysfunction J Am Coll Cardiol 2003411078ndash1083

145 Shiba Y Gomibuchi T Seto T Wada Y Ichimura H Tanaka Y Ogasawara T OkadaK Shiba N Sakamoto K Ido D Shiina T Ohkura M Nakai J Uno N Kazuki YOshimura M Minami I Ikeda U Allogeneic transplantation of iPS cell-derived cardi-omyocytes regenerates primate hearts Nature 2016538388ndash391

146 Liu Y-W Chen B Yang X Fugate JA Kalucki FA Futakuchi-Tsuchida A Couture LVogel KW Astley CA Baldessari A Ogle J Don CW Steinberg ZL Seslar SP TuckSA Tsuchida H Naumova AV Dupras SK Lyu MS Lee J Hailey DW Reinecke HPabon L Fryer BH MacLellan WR Thies RS Murry CE Human embryonic stemcell-derived cardiomyocytes restore function in infarcted hearts of non-human pri-mates Nat Biotechnol 201836597ndash605

147 Madonna R Human-induced pluripotent stem cells in quest of clinical applicationsMol Biotechnol 201252193ndash203

148 Breitbach M Bostani T Roell W Xia Y Dewald O Nygren JM Fries JWU TiemannK Bohlen H Hescheler J Welz A Bloch W Jacobsen SEW Fleischmann BKPotential risks of bone marrow cell transplantation into infarcted hearts Blood20071101362ndash1369

149 Chung L Maestas DR Jr Housseau F Elisseeff JH Key players in the immune re-sponse to biomaterial scaffolds for regenerative medicine Adv Drug Deliv Rev 2017114184ndash192

150 Natsumeda M Florea V Rieger AC Tompkins BA Banerjee MN Golpanian SFritsch J Landin AM Kashikar ND Karantalis V Loescher VY Hatzistergos KEBagno L Sanina C Mushtaq M Rodriguez J Rosado M Wolf A Collon K VincentL Kanelidis AJ Schulman IH Mitrani R Heldman AW Balkan W Hare JM A combi-nation of allogeneic stem cells promotes cardiac regeneration J Am Coll Cardiol2017702504ndash2515

151 Marks P Gottlieb S Balancing safety and innovation for cell-based regenerativemedicine N Engl J Med 2018378954ndash959

500 R Madonna et alD

ownloaded from

httpsacademicoupcom

cardiovascresarticle-abstract11534885292411 by University of C

ape Town Libraries user on 26 April 2019

79 Sun J Lu Y Huang Y Zhang L Ma Y Engineered heart tissue transplantation alters

electrical-conduction function in rats with myocardial infarction Life Sci 201411834ndash38

80 Yanamandala M Zhu W Garry DJ Kamp TJ Hare JM Jun H-W Yoon Y-S BursacN Prabhu SD Dorn GW Bolli R Kitsis RN Zhang J Overcoming the roadblocksto cardiac cell therapy using tissue engineering J Am Coll Cardiol 201770766ndash775

81 Seif-Naraghi SB Singelyn JM Salvatore MA Osborn KG Wang JJ Sampat U KwanOL Strachan GM Wong J Schup-Magoffin PJ Braden RL Bartels K DeQuach JAPreul M Kinsey AM DeMaria AN Dib N Christman KL Safety and efficacy of aninjectable extracellular matrix hydrogel for treating myocardial infarction Sci TranslMed 20135173ra25

82 Dawson E Mapili G Erickson K Taqvi S Roy K Biomaterials for stem cell differenti-ation Adv Drug Deliv Rev 200860215ndash228

83 Nawroth JC Scudder LL Halvorson RT Tresback J Ferrier JP Sheehy SP Cho AKannan S Sunyovszki I Goss JA Campbell PH Parker KK Automated fabrication ofphotopatterned gelatin hydrogels for organ-on-chips applications Biofabrication201810025004

84 Shin SR Jung SM Zalabany M Kim K Zorlutuna P Kim S B Nikkhah M Khabiry MAzize M Kong J Wan K-T Palacios T Dokmeci MR Bae H Tang X(S)Khademhosseini A Carbon-nanotube-embedded hydrogel sheets for engineeringcardiac constructs and bioactuators ACS Nano 201372369ndash2380

85 Mosqueira D Pagliari S Uto K Ebara M Romanazzo S Escobedo-Lucea CNakanishi J Taniguchi A Franzese O Di Nardo P Goumans MJ Traversa E Pinto-do-O P Aoyagi T Forte G Hippo pathway effectors control cardiac progenitor cellfate by acting as dynamic sensors of substrate mechanics and nanostructure ACSNano 201482033ndash2047

86 Yue K Trujillo-de Santiago G Alvarez MM Tamayol A Annabi N KhademhosseiniA Synthesis properties and biomedical applications of gelatin methacryloyl(GelMA) hydrogels Biomaterials 201573254ndash271

87 Tiburcy M Didie M Boy O Christalla P Doker S Naito H Karikkineth BC El-Armouche A Grimm M Nose M Eschenhagen T Zieseniss A Katschinksi DMHamdani N Linke WA Yin X Mayr M Zimmermann W-H Terminal differentia-tion advanced organotypic maturation and modeling of hypertrophic growth inengineered heart tissue Circ Res 20111091105ndash1114

88 Shimizu T Sekine H Yang J Isoi Y Yamato M Kikuchi A Kobayashi E Okano TPolysurgery of cell sheet grafts overcomes diffusion limits to produce thick vascu-larized myocardial tissues FASEB J 200620708ndash710

89 Yang J Yamato M Nishida K Ohki T Kanzaki M Sekine H Shimizu T Okano TCell delivery in regenerative medicine the cell sheet engineering approach J ControlRelease 2006116193ndash203

90 Miyahara Y Nagaya N Kataoka M Yanagawa B Tanaka K Hao H Ishino K IshidaH Shimizu T Kangawa K Sano S Okano T Kitamura S Mori H Monolayered mes-enchymal stem cells repair scarred myocardium after myocardial infarction NatMed 200612459ndash465

91 Narita T Shintani Y Ikebe C Kaneko M Campbell NG Coppen SR Uppal R SawaY Yashiro K Suzuki K The use of scaffold-free cell sheet technique to refine mes-enchymal stromal cell-based therapy for heart failure Mol Ther 201321860ndash867

92 Masumoto H Matsuo T Yamamizu K Uosaki H Narazaki G Katayama S Marui AShimizu T Ikeda T Okano T Sakata R Yamashita JK Pluripotent stem cell-engineered cell sheets reassembled with defined cardiovascular populations amelio-rate reduction in infarct heart function through cardiomyocyte-mediated neovascu-larization Stem Cells 2012301196ndash1205

93 Sawa Y Yoshikawa Y Toda K Fukushima S Yamazaki K Ono M Sakata YHagiwara N Kinugawa K Miyagawa S Safety and efficacy of autologous skeletalmyoblast sheets (TCD-51073) for the treatment of severe chronic heart failure dueto ischemic heart disease Circ J 201579991ndash999

94 Cyranoski D lsquoReprogrammedrsquo stem cells approved to mend human hearts for thefirst time Nature 2018557619ndash620

95 Shimizu T Yamato M Isoi Y Akutsu T Setomaru T Abe K Kikuchi A Umezu MOkano T Fabrication of pulsatile cardiac tissue grafts using a novel 3-dimensionalcell sheet manipulation technique and temperature-responsive cell culture surfacesCirc Res 200290e40

96 Groll J Boland T Blunk T Burdick JA Cho D-W Dalton PD Derby B Forgacs GLi Q Mironov VA Moroni L Nakamura M Shu W Takeuchi S Vozzi G WoodfieldTBF Xu T Yoo JJ Malda J Biofabrication reappraising the definition of an evolvingfield Biofabrication 20168013001

97 Cui H Miao S Esworthy T Zhou X Lee SJ Liu C Yu ZX Fisher JP Mohiuddin MZhang LG 3D bioprinting for cardiovascular regeneration and pharmacology AdvDrug Deliv Rev 2018132252ndash269

98 Bejleri D Streeter BW Nachlas ALY Brown ME Gaetani R Christman KL DavisME A bioprinted cardiac patch composed of cardiac-specific extracellular matrixand progenitor cells for heart repair Adv Healthc Mater 201871800672

99 Ionov L 4D biofabrication materials methods and applications Adv Healthc Mater201871800412

100 Schaefer JA Guzman PA Riemenschneider SB Kamp TJ Tranquillo RT A cardiacpatch from aligned microvessel and cardiomyocyte patches J Tissue Eng Regen Med201812546ndash556

101 Jackman CP Ganapathi AM Asfour H Qian Y Allen BW Li Y Bursac NEngineered cardiac tissue patch maintains structural and electrical properties afterepicardial implantation Biomaterials 201815948ndash58

102 Dvir T Timko BP Brigham MD Naik SR Karajanagi SS Levy O Jin H Parker KKLanger R Kohane DS Nanowired three-dimensional cardiac patches NatNanotechnol 20116720ndash725

103 Boothe SD Myers JD Pok S Sun J Xi Y Nieto RM Cheng J Jacot JG The effect ofsubstrate stiffness on cardiomyocyte action potentials Cell Biochem Biophys 201674527ndash535

104 Roeder I Loeffler M Glauche I Other P Towards a quantitative understanding ofstem cell-niche interaction experiments models and technologies Blood Cells MolDis 201146308ndash317

105 Chimenti I Massai D Morbiducci U Beltrami AP Pesce M Messina E Stem cellspheroids and ex vivo niche modeling rationalization and scaling-up J CardiovascTransl Res 201710150ndash166

106 Montgomery M Ahadian S Davenport Huyer L Lo Rito M Civitarese RAVanderlaan RD Wu J Reis LA Momen A Akbari S Pahnke A Li R-K CaldaroneCA Radisic M Flexible shape-memory scaffold for minimally invasive delivery offunctional tissues Nat Mater 2017161038ndash1046

107 Sepantafar M Maheronnaghsh R Mohammadi H Rajabi-Zeleti S Annabi NAghdami N Baharvand H Stem cells and injectable hydrogels synergistic therapeu-tics in myocardial repair Biotechnol Adv 201634362ndash379

108 Madonna R Petrov L Teberino MA Manzoli L Karam J-P Renna FV Ferdinandy PMontero-Menei CN Yla-Herttuala S De Caterina R Transplantation of adipose tis-sue mesenchymal cells conjugated with VEGF-releasing microcarriers promotes re-pair in murine myocardial infarction Cardiovasc Res 201510839ndash49

109 Wang LL Liu Y Chung JJ Wang T Gaffey AC Lu M Cavanaugh CA Zhou SKanade R Atluri P Morrisey EE Burdick JA Local and sustained miRNA deliveryfrom an injectable hydrogel promotes cardiomyocyte proliferation and functionalregeneration after ischemic injury Nat Biomed Eng 20171983ndash992

110 Waters R Alam P Pacelli S Chakravarti AR Ahmed RPH Paul A Stem cell-inspired secretome-rich injectable hydrogel to repair injured cardiac tissue ActaBiomater 20186995ndash106

111 Liu H Paul C Xu M Optimal environmental stiffness for stem cell mediated ische-mic myocardium repair Methods Mol Biol 20171553293ndash304

112 Bao R Tan B Liang S Zhang N Wang W Liu W A pi-pi conjugation-containingsoft and conductive injectable polymer hydrogel highly efficiently rebuilds cardiacfunction after myocardial infarction Biomaterials 201712263ndash71

113 Morez C Noseda M Paiva MA Belian E Schneider MD Stevens MM Enhanced effi-ciency of genetic programming toward cardiomyocyte creation through topographi-cal cues Biomaterials 20157094ndash104

114 Ebrahimi B In vivo reprogramming for heart regeneration a glance at efficiency envi-ronmental impacts challenges and future directions J Mol Cell Cardiol 201710861ndash72

115 Song Y Zhang C Zhang J Sun N Huang K Li H Wang Z Huang K Wang L An in-jectable silk sericin hydrogel promotes cardiac functional recovery after ischemicmyocardial infarction Acta Biomater 201641210ndash223

116 Kim BH Park M Park HJ Lee SH Choi SY Park CG Han SM Heo CY Choy YBProlonged acute suppression of cysteinyl leukotriene to reduce capsular contrac-ture around silicone implants Acta Biomater 201751209ndash219

117 Kimura W Xiao F Canseco DC Muralidhar S Thet S Zhang HM Abderrahman YChen R Garcia JA Shelton JM Richardson JA Ashour AM Asaithamby A Liang HXing C Lu Z Zhang CC Sadek HA Hypoxia fate mapping identifies cycling cardio-myocytes in the adult heart Nature 2015523226ndash230

118 Vishwakarma A Bhise NS Evangelista MB Rouwkema J Dokmeci MRGhaemmaghami AM Vrana NE Khademhosseini A Engineering immunomodulatorybiomaterials to tune the inflammatory response Trends Biotechnol 201634470ndash482

119 Aurora AB Porrello ER Tan W Mahmoud AI Hill JA Bassel-Duby R Sadek HAOlson EN Macrophages are required for neonatal heart regeneration J Clin Invest20141241382ndash1392

120 Hernandez MJ Christman KL Designing acellular injectable biomaterial therapeuticsfor treating myocardial infarction and peripheral artery disease JACC Basic Transl Sci20172212ndash226

121 Mann DL Lee RJ Coats AJS Neagoe G Dragomir D Pusineri E Piredda M BettariL Kirwan B-A Dowling R Volterrani M Solomon SD Sabbah HN Hinson AAnker SD One-year follow-up results from AUGMENT-HF a multicentre random-ized controlled clinical trial of the efficacy of left ventricular augmentation withAlgisyl in the treatment of heart failure Eur J Heart Fail 201618314ndash325

122 Anker SD Coats AJS Cristian G Dragomir D Pusineri E Piredda M Bettari LDowling R Volterrani M Kirwan B-A Filippatos G Mas J-L Danchin N SolomonSD Lee RJ Ahmann F Hinson A Sabbah HN Mann DL A prospective comparisonof alginate-hydrogel with standard medical therapy to determine impact on func-tional capacity and clinical outcomes in patients with advanced heart failure(AUGMENT-HF trial) Eur Heart J 2015362297ndash2309

123 Frey N Linke A Suselbeck T Muller-Ehmsen J Vermeersch P Schoors DRosenberg M Bea F Tuvia S Leor J Intracoronary delivery of injectable bioabsorb-able scaffold (IK-5001) to treat left ventricular remodeling after ST-elevation myo-cardial infarction a first-in-man study Circ Cardiovasc Interv 20147806ndash812

Tissue engineering and cell-based therapies for cardiac repair in ischaemic heart disease and heart failure 499D

ownloaded from

httpsacademicoupcom

cardiovascresarticle-abstract11534885292411 by University of C

ape Town Libraries user on 26 April 2019

124 Wei K Serpooshan V Hurtado C Diez-Cu~nado M Zhao M Maruyama S Zhu W

Fajardo G Noseda M Nakamura K Tian X Liu Q Wang A Matsuura Y BushwayP Cai W Savchenko A Mahmoudi M Schneider MD van den Hoff MJB Butte MJYang PC Walsh K Zhou B Bernstein D Mercola M Ruiz-Lozano P EpicardialFSTL1 reconstitution regenerates the adult mammalian heart Nature 2015525479ndash485

125 Sluijter JPG Davidson SM Boulanger CM Buzas EI de Kleijn DPV Engel FB GiriczZ Hausenloy DJ Kishore R Lecour S Leor J Madonna R Perrino C Prunier FSahoo S Schiffelers RM Schulz R Van Laake LW Ytrehus K Ferdinandy PExtracellular vesicles in diagnostics and therapy of the ischaemic heart positionPaper from the Working Group on Cellular Biology of the Heart of the EuropeanSociety of Cardiology Cardiovasc Res 201811419ndash34

126 Barile L Cervio E Lionetti V Milano G Ciullo A Biemmi V Bolis S Altomare CMatteucci M Di Silvestre D Brambilla F Fertig TE Torre T Demertzis S Mauri PMoccetti T Vassalli G Cardioprotection by cardiac progenitor cell-secreted exo-somes role of pregnancy-associated plasma protein-A Cardiovasc Res 2018114992ndash1005

127 El Harane N Kervadec A Bellamy V Pidial L Neametalla HJ Perier MC LimaCorrea B Thiebault L Cagnard N Duche A Brunaud C Lemitre M Gauthier JBourdillon AT Renault MP Hovhannisyan Y Paiva S Colas AR Agbulut O HagegeA Silvestre JS Menasche P Renault NKE Acellular therapeutic approach for heartfailure in vitro production of extracellular vesicles from human cardiovascular pro-genitors Eur Heart J 2018391835ndash1847

128 Chen CW Wang LL Zaman S Gordon J Arisi MF Venkataraman CM Chung JJHung G Gaffey AC Spruce LA Fazelinia H Gorman RC Seeholzer SH Burdick JAAtluri P Sustained release of endothelial progenitor cell-derived extracellularvesicles from shear-thinning hydrogels improves angiogenesis and promotes func-tion after myocardial infarction Cardiovasc Res 20181141029ndash1040

129 Pape AC Bakker MH Tseng CC Bastings MM Koudstaal S Agostoni P ChamuleauSA Dankers PY An injectable and drug-loaded supramolecular hydrogel for localcatheter injection into the pig heart J Vis Exp 2015e52450

130 Koudstaal S Bastings MMC Feyen DAM Waring CD van Slochteren FJ DankersPYW Torella D Sluijter JPG Nadal-Ginard B Doevendans PA Ellison GMChamuleau SAJ Sustained delivery of insulin-like growth factor-1hepatocytegrowth factor stimulates endogenous cardiac repair in the chronic infarcted pigheart J Cardiovasc Transl Res 20147232ndash241

131 Hastings CL Roche ET Ruiz-Hernandez E Schenke-Layland K Walsh CJ DuffyGP Drug and cell delivery for cardiac regeneration Adv Drug Deliv Rev 20158485ndash106

132 Gathier WA van Ginkel DJ van der Naald M van Slochteren FJ Doevendans PAChamuleau SAJ Retrograde coronary venous infusion as a delivery strategy in re-generative cardiac therapy an overview of preclinical and clinical data J CardiovascTransl Res 201811173ndash181

133 Tang XL Nakamura S Li Q Wysoczynski M Gumpert AM Wu WJ Hunt GStowers H Ou Q Bolli R Repeated administrations of cardiac progenitor cells aresuperior to a single administration of an equivalent cumulative dose J Am HeartAssoc 20187piie007400

134 Chaudhuri R Ramachandran M Moharil P Harumalani M Jaiswal AK Biomaterialsand cells for cardiac tissue engineering current choices Mater Sci Eng C Mater BiolAppl 201779950ndash957

135 Bel A Planat-Bernard V Saito A Bonnevie L Bellamy V Sabbah L Bellabas LBrinon B Vanneaux V Pradeau P Peyrard S Larghero J Pouly J Binder P Garcia SShimizu T Sawa Y Okano T Bruneval P Desnos M Hagege AA Casteilla L PuceatM Menasche P Composite cell sheets a further step toward safe and effectivemyocardial regeneration by cardiac progenitors derived from embryonic stem cellsCirculation 2010122S118ndashS123

136 Kawatou M Masumoto H Fukushima H Morinaga G Sakata R Ashihara TYamashita JK Modelling Torsade de Pointes arrhythmias in vitro in 3D human iPScell-engineered heart tissue Nat Commun 201781078

137 Qi C Yan X Huang C Melerzanov A Du Y Biomaterials as carrier barrier and re-actor for cell-based regenerative medicine Protein Cell 20156638ndash653

138 Kempf H Kropp C Olmer R Martin U Zweigerdt R Cardiac differentiation of humanpluripotent stem cells in scalable suspension culture Nat Protoc 2015101345ndash1361

139 Rojas SV Kensah G Rotaermel A Baraki H Kutschka I Zweigerdt R Martin UHaverich A Gruh I Martens A Transplantation of purified iPSC-derived cardiomyo-cytes in myocardial infarction PLoS One 201712e0173222

140 Chachques JC Trainini JC Lago N Cortes-Morichetti M Schussler O CarpentierA Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium(MAGNUM trial) clinical feasibility study Ann Thorac Surg 200885901ndash908

141 Ferdinandy P Hausenloy DJ Heusch G Baxter GF Schulz R Interaction of risk fac-tors comorbidities and comedications with ischemiareperfusion injury and cardio-protection by preconditioning postconditioning and remote conditioningPharmacol Rev 2014661142ndash1174

142 Hausenloy DJ Garcia-Dorado D Boslashtker HE Davidson SM Downey J Engel FBJennings R Lecour S Leor J Madonna R Ovize M Perrino C Prunier F Schulz RSluijter JPG Van Laake LW Vinten-Johansen J Yellon DM Ytrehus K Heusch GFerdinandy P Novel targets and future strategies for acute cardioprotection posi-tion Paper of the European Society of Cardiology Working Group on CellularBiology of the Heart Cardiovasc Res 2017113564ndash585

143 Corbett MS Webster A Hawkins R Woolacott N Innovative regenerative medi-cines in the EU a better future in evidence BMC Med 20171549

144 Menasche P Hagege AA Vilquin J-T Desnos M Abergel E Pouzet B Bel ASarateanu S Scorsin M Schwartz K Bruneval P Benbunan M Marolleau J-P DubocD Autologous skeletal myoblast transplantation for severe postinfarction left ven-tricular dysfunction J Am Coll Cardiol 2003411078ndash1083

145 Shiba Y Gomibuchi T Seto T Wada Y Ichimura H Tanaka Y Ogasawara T OkadaK Shiba N Sakamoto K Ido D Shiina T Ohkura M Nakai J Uno N Kazuki YOshimura M Minami I Ikeda U Allogeneic transplantation of iPS cell-derived cardi-omyocytes regenerates primate hearts Nature 2016538388ndash391

146 Liu Y-W Chen B Yang X Fugate JA Kalucki FA Futakuchi-Tsuchida A Couture LVogel KW Astley CA Baldessari A Ogle J Don CW Steinberg ZL Seslar SP TuckSA Tsuchida H Naumova AV Dupras SK Lyu MS Lee J Hailey DW Reinecke HPabon L Fryer BH MacLellan WR Thies RS Murry CE Human embryonic stemcell-derived cardiomyocytes restore function in infarcted hearts of non-human pri-mates Nat Biotechnol 201836597ndash605

147 Madonna R Human-induced pluripotent stem cells in quest of clinical applicationsMol Biotechnol 201252193ndash203

148 Breitbach M Bostani T Roell W Xia Y Dewald O Nygren JM Fries JWU TiemannK Bohlen H Hescheler J Welz A Bloch W Jacobsen SEW Fleischmann BKPotential risks of bone marrow cell transplantation into infarcted hearts Blood20071101362ndash1369

149 Chung L Maestas DR Jr Housseau F Elisseeff JH Key players in the immune re-sponse to biomaterial scaffolds for regenerative medicine Adv Drug Deliv Rev 2017114184ndash192

150 Natsumeda M Florea V Rieger AC Tompkins BA Banerjee MN Golpanian SFritsch J Landin AM Kashikar ND Karantalis V Loescher VY Hatzistergos KEBagno L Sanina C Mushtaq M Rodriguez J Rosado M Wolf A Collon K VincentL Kanelidis AJ Schulman IH Mitrani R Heldman AW Balkan W Hare JM A combi-nation of allogeneic stem cells promotes cardiac regeneration J Am Coll Cardiol2017702504ndash2515

151 Marks P Gottlieb S Balancing safety and innovation for cell-based regenerativemedicine N Engl J Med 2018378954ndash959

500 R Madonna et alD

ownloaded from

httpsacademicoupcom

cardiovascresarticle-abstract11534885292411 by University of C

ape Town Libraries user on 26 April 2019

124 Wei K Serpooshan V Hurtado C Diez-Cu~nado M Zhao M Maruyama S Zhu W

Fajardo G Noseda M Nakamura K Tian X Liu Q Wang A Matsuura Y BushwayP Cai W Savchenko A Mahmoudi M Schneider MD van den Hoff MJB Butte MJYang PC Walsh K Zhou B Bernstein D Mercola M Ruiz-Lozano P EpicardialFSTL1 reconstitution regenerates the adult mammalian heart Nature 2015525479ndash485

125 Sluijter JPG Davidson SM Boulanger CM Buzas EI de Kleijn DPV Engel FB GiriczZ Hausenloy DJ Kishore R Lecour S Leor J Madonna R Perrino C Prunier FSahoo S Schiffelers RM Schulz R Van Laake LW Ytrehus K Ferdinandy PExtracellular vesicles in diagnostics and therapy of the ischaemic heart positionPaper from the Working Group on Cellular Biology of the Heart of the EuropeanSociety of Cardiology Cardiovasc Res 201811419ndash34

126 Barile L Cervio E Lionetti V Milano G Ciullo A Biemmi V Bolis S Altomare CMatteucci M Di Silvestre D Brambilla F Fertig TE Torre T Demertzis S Mauri PMoccetti T Vassalli G Cardioprotection by cardiac progenitor cell-secreted exo-somes role of pregnancy-associated plasma protein-A Cardiovasc Res 2018114992ndash1005

127 El Harane N Kervadec A Bellamy V Pidial L Neametalla HJ Perier MC LimaCorrea B Thiebault L Cagnard N Duche A Brunaud C Lemitre M Gauthier JBourdillon AT Renault MP Hovhannisyan Y Paiva S Colas AR Agbulut O HagegeA Silvestre JS Menasche P Renault NKE Acellular therapeutic approach for heartfailure in vitro production of extracellular vesicles from human cardiovascular pro-genitors Eur Heart J 2018391835ndash1847

128 Chen CW Wang LL Zaman S Gordon J Arisi MF Venkataraman CM Chung JJHung G Gaffey AC Spruce LA Fazelinia H Gorman RC Seeholzer SH Burdick JAAtluri P Sustained release of endothelial progenitor cell-derived extracellularvesicles from shear-thinning hydrogels improves angiogenesis and promotes func-tion after myocardial infarction Cardiovasc Res 20181141029ndash1040

129 Pape AC Bakker MH Tseng CC Bastings MM Koudstaal S Agostoni P ChamuleauSA Dankers PY An injectable and drug-loaded supramolecular hydrogel for localcatheter injection into the pig heart J Vis Exp 2015e52450

130 Koudstaal S Bastings MMC Feyen DAM Waring CD van Slochteren FJ DankersPYW Torella D Sluijter JPG Nadal-Ginard B Doevendans PA Ellison GMChamuleau SAJ Sustained delivery of insulin-like growth factor-1hepatocytegrowth factor stimulates endogenous cardiac repair in the chronic infarcted pigheart J Cardiovasc Transl Res 20147232ndash241

131 Hastings CL Roche ET Ruiz-Hernandez E Schenke-Layland K Walsh CJ DuffyGP Drug and cell delivery for cardiac regeneration Adv Drug Deliv Rev 20158485ndash106

132 Gathier WA van Ginkel DJ van der Naald M van Slochteren FJ Doevendans PAChamuleau SAJ Retrograde coronary venous infusion as a delivery strategy in re-generative cardiac therapy an overview of preclinical and clinical data J CardiovascTransl Res 201811173ndash181

133 Tang XL Nakamura S Li Q Wysoczynski M Gumpert AM Wu WJ Hunt GStowers H Ou Q Bolli R Repeated administrations of cardiac progenitor cells aresuperior to a single administration of an equivalent cumulative dose J Am HeartAssoc 20187piie007400

134 Chaudhuri R Ramachandran M Moharil P Harumalani M Jaiswal AK Biomaterialsand cells for cardiac tissue engineering current choices Mater Sci Eng C Mater BiolAppl 201779950ndash957

135 Bel A Planat-Bernard V Saito A Bonnevie L Bellamy V Sabbah L Bellabas LBrinon B Vanneaux V Pradeau P Peyrard S Larghero J Pouly J Binder P Garcia SShimizu T Sawa Y Okano T Bruneval P Desnos M Hagege AA Casteilla L PuceatM Menasche P Composite cell sheets a further step toward safe and effectivemyocardial regeneration by cardiac progenitors derived from embryonic stem cellsCirculation 2010122S118ndashS123

136 Kawatou M Masumoto H Fukushima H Morinaga G Sakata R Ashihara TYamashita JK Modelling Torsade de Pointes arrhythmias in vitro in 3D human iPScell-engineered heart tissue Nat Commun 201781078

137 Qi C Yan X Huang C Melerzanov A Du Y Biomaterials as carrier barrier and re-actor for cell-based regenerative medicine Protein Cell 20156638ndash653

138 Kempf H Kropp C Olmer R Martin U Zweigerdt R Cardiac differentiation of humanpluripotent stem cells in scalable suspension culture Nat Protoc 2015101345ndash1361

139 Rojas SV Kensah G Rotaermel A Baraki H Kutschka I Zweigerdt R Martin UHaverich A Gruh I Martens A Transplantation of purified iPSC-derived cardiomyo-cytes in myocardial infarction PLoS One 201712e0173222

140 Chachques JC Trainini JC Lago N Cortes-Morichetti M Schussler O CarpentierA Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium(MAGNUM trial) clinical feasibility study Ann Thorac Surg 200885901ndash908

141 Ferdinandy P Hausenloy DJ Heusch G Baxter GF Schulz R Interaction of risk fac-tors comorbidities and comedications with ischemiareperfusion injury and cardio-protection by preconditioning postconditioning and remote conditioningPharmacol Rev 2014661142ndash1174

142 Hausenloy DJ Garcia-Dorado D Boslashtker HE Davidson SM Downey J Engel FBJennings R Lecour S Leor J Madonna R Ovize M Perrino C Prunier F Schulz RSluijter JPG Van Laake LW Vinten-Johansen J Yellon DM Ytrehus K Heusch GFerdinandy P Novel targets and future strategies for acute cardioprotection posi-tion Paper of the European Society of Cardiology Working Group on CellularBiology of the Heart Cardiovasc Res 2017113564ndash585

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