Waiting for the heart transplant

The first cardiac transplant from America took place at The Stanford Health Care . The experts in the same institute nowadays push the boundaries of science to save lives . They suggest that the total artificial heart is an intermediate option for the patients with right or bi - ventricular failure .

The longitudinal monitoring for the myocardium

The imaging techniques , in suitable parameters , provide the connection between the cell therapies and the clinical procedure . The longitudinal monitoring provides information about the functioning mechanism of the reprogrammed cells in the in vivo environment . The review presents the imaging techniques that are able to explain the cause for the limited restoration process of the cell therapies in the cardiac tissue .

The human body contains approximately 3 , 7 × 10¹³ cells . The heart contains 6 × 10⁹ cells , in 300 grams ( figure 1 ) . The damage of the heart does not lead automatically to the regeneration of the full functional capacity . The scar formation and the inflammatory signals may not be enough to have a full regeneration of the cardiac tissue . The regenerative medicine enhances the healing mechanisms of the body with the cell therapy .

Figure 1 . The number of cells in the parts of the human body .
Copyright ( 2014 ) Katie Vicari / Nature Publishing Group

The minimum number of injected cells that is detectable by the imaging techniques is in the range of 10⁴ - 10⁶ cells . The heart contains 2 × 10⁷ cells in one gram of tissue , in the left ventricle . The fused positron emission tomography ( PET ) - computed tomography ( CT ) image of the porcine heart is an example for the technique ( figure 2 ) . The long arrows point to the trajectory of the thoracotomy . T is the inserted tube . The short arrows point to the 10⁸ human mesenchymal stem cells , injected in the left ventricle ( LV ) . The %ID / g is the percentage of the uptake by the injected human cells in one gram of porcine cardiac tissue .

Figure 2 . The PET - CT imaging of the expression for the reporter gene in the porcine myocardium .
Copyright ( 2009 ) RSNA

The results of a porcine model for the myocardial infarction identifies as the time for the maximum proliferation at an interval of 33 - 35 days after the injection of the mesenchymal stem cells in the myocardium .

The injected cells are not tracked in vivo if they are not labelled in vitro . The nanoparticles , as the exogeneous label , provide a strong contrast in a short acquisition time , but it is unreliable in the long - term monitoring . The incorporation process of reporter genes labels indirectly the target cell . The reporter gene in the nucleus creates reporter proteins secreted in the cytoplasm . The imaging technique detects the reporter proteins . The ideal cell label stays inside the target cells for a long time , is non - toxic , is in a concentration that is stoichiometric related to the number of target cells , and clears the system rapidly after the apoptosis of the target cells .

The challenges of the imaging techniques are the label dilution , and the cell tracking . The label dilution should remain inside the tracked cells until the apoptosis , but sometimes the dilution transfers to the host cells . The long - term tracking of the implanted cells through the imaging techniques has the challenge to quantify the number of cells from the initial implantation procedure that are alive , and the number of cells that proliferate , in the spatial and the temporal dimension .

The infarcted myocardium is trully regenerated with the aid from the cell therapies when the viable cardiac tissue in the infarct area has the volume increased , the fiber architecture is integer in structure , and the regenerated myocardium has synchronous contraction with the host .

References :

Naumova A . V . , Modo M . , Moore A . , Murry C . E . , Frank J . A . ( 2014 ) “ Clinical imaging in regenerative medicine ” , Nature Biotechnology , 32 ( 8 ) , 804 - 818 .

Willmann J . K . , Paulmurugan R . , Rodriguez - Porcel M . , Stein W . , Brinton T . J . , Connolly A . J . , Nielsen C . H . , Lutz A . M . , Lyons J . , Ikeno F . , Suzuki Y . , Rosenberg J . , Chen I . Y . , Wu J . C . , Yeung A . C . , Yock P . , Robbins R . C . , Gambhir S . S . ( 2009 ) “ Imaging gene expression in human mesenchymal stem cells : from small to large animals ” , Radiology - Radiological Society of North America , 252 ( 1 ) , 117 - 127 .

The effects on the heart after the replacement for the mitral valve

The echocardiographic investigation of the mitral valve shows which leaflet is degenerated , if the leaflet , and the ring , maintained the integrity , the state of the attachment for the chorda tendinae , the structure of the papillary muscles . Two follow - up studies present the outcome of the mitral valvuloplasty for the elderly patients .

A study presents the clinical findings for a man of 74 years old . He did not have regurgitation of the tricuspid valve before he had a prosthetic replacement for the mitral valve . The left side of the heart stabilised with the surgery . The aortic valve had an unaffected functioning mechanism . The postoperative atrial fibrillation progressed. The postoperative regurgitation of the tricuspid valve made an impact on the right side of the heart .

The rheumatic heart disease ( RHD ) , and the dilated cardiomyopathy ( DCM ) are the causes for the stenosis ( MS ) , and for the regurgitation ( MR ) of the mitral valve ( figure 1 ) . The effects of the increased pressure in the left atrium are the increased size of the left atrium , the atrial fibrillation , and the pulmonary hypertension . The atrial fibrillation produces the dilation for the ring of the tricuspid valve . The pulmonary hypertension generates the dilation of the right ventricle ( RV ) . The regurgitation of the tricuspid valve ( TV ) worsens the tethering of the tricuspid valve , and the dilation of the right ventricle .

Figure 1 . The regurgitation of the tricuspid valve after the mitral valvuloplasty . Copyright ( 2009 ) Journal of The American College of Cardiology .

Another follow - up study analyses the clinical outcome for 242 patients who had valvuloplasty for the repair of the mitral valve . The patients are free from the non - trivial regurgitation of the mitral valve in 94 . 3 ± 1 . 6 % after one month , 58 . 6 ± 4 . 9 % after five years , and 27 . 2 ± 8 . 6 % after seven years ( figure 2 ) . The freedom from the severe regurgitation of the mitral valve is 98 . 3 ± 0 . 9 % after one month , 82 . 8 ± 3 . 8 % after five years , and 71 . 1 ± 7 . 4 % after seven years .

Figure 2 . The non - trivial regurgitation of the mitral valve . Copyright ( 2003 ) Circulation .

The dysfunction of the mitral valve is generated by the rheumatic heart disease , by the ischemic heart disease , and by the bacterial endocarditis . The succes of the replacement for the mitral valve is assessed both in the short term , and in the long term effects on the quality of life for the patient .

References :

Flameng W . , Herijgers P . , Bogaers K . ( 2003 ) “ The clinical anatomy and pathology of the human arterial valves : implications for repair or replacement ” , Circulation , 107 , 1609 - 1613 .

Shiran A . , Sagie A . ( 2009 ) “ Tricuspid regurgitation in mitral valve disease : incidence , prognostic implications , mechanism , and management ” , Journal of The American College of Cardiology , 53 ( 5 ) , 401 - 408 .

Features of the pulmonary valve

The aortic and the pulmonary valves are anatomical structures of high complexity . The assessment , and the treatment methodology is developed for the disorders of the two semilunar , tricuspid valves . The proper functioning mechanism of the semilunar valve is represented by the closed phase during systole , and the open one during diastole ( figure 1 ) . The valve stenosis is generated by the inability of the valve to open successfully . The regurgitation of the blood is caused by the incapacitation of the valve to close shut .

Figure 1 . The internal videoscopic view of the pulmonary valve in the reanimated human heart , sagittal superior ( a , b ) , sagital inferior ( c , d ) , in systole ( a , c ) , in diastole ( b , d ) . Copyright ( 2013 ) Springer .

The three dimensional arrangement of the pulmonary valve is maintained by the histological structure designed with the fibrosa , the spongiosa , and The Nodulus Arantii ( figure 2 ) . The mean value for the annular diameter of the pulmonary valve is 25 . 4 ± 3 . 2 ( N = 3997 ) , and the mean value for the aortic valve is 22 . 4 ± 2 . 7 ( N = 3370 ) .

Figure 2 . The idealised three - dimensional structure of the semilunar valve . Copyright ( 2013 ) Journal of Cardiovascular Translational Research .

The surgery on the pulmonary valve presents less risk because the pressure gradient across the valve is low , comparing to the one for the aortic valve . Both the pulmonary and the aortic valve have similar dimensions , with slightly different material properties ( figure 3 ) . The pulmonary valve is considered as autograft replacement for the aortic valve in some patients with congenital heart disorders .

Figure 3 . The name of the leaflets for the semilunar valves . Copyright ( 2013 ) Springer .

Four of the 3861 hearts analysed by The European Homograft Bank have the pulmonary valve with two leaflets . Eight of the 109571 autopsies present an aneurysm of the pulmonary artery . A patient with both these conditions may have had an anomaly in the embryonic development .

References :

Batesman M . G . , Hill A . J . , Quill J . L . , Iaizzo P . A . ( 2013 ) “ The clinical anatomy and pathology of the human arterial valves : implications for repair or replacement ” , Journal of Cardiovascular Translational Research , 6 ( 2 ) , 166 - 175 .

Capps S . B . , Elkins R . C . , Fronk D . M . ( 2000 ) “ Body surface area as a predictor of aortic and pulmonary valve diameter ” , The Journal of Thoracic and Cardiovascular Surgery , 119 , 975 - 982 .

Iaizzo P . A . , Bianco R . W . , Hill A . J . , Louis J . D . S . ( 2013 ) “ Heart valves : from design to clinical implantation ” , Springer , part I . 2 , 27 - 45 .

The postoperative atrial fibrillation

The fast and irregular flow of the blood reduces the efficiency of the heart . The incidence of atrial fibrillation after cardiac surgery is 18.8 % of 49 264 patients , from the database between 2001 until 2012 in The Virginia Cardiac Surgery Quality Initiative . It is the cause of one in five strokes , and it reduces the quality of life . When it occurs after heart surgery , the risk of symptomatic hypotension , thromboembolism and heart failure is increased .

The European Society of Cardiology published guidelines for the control of the ventricular rate . There are five types of clinical symptoms for atrial fibrillation ( AF ), based on the time length : newly diagnosed , paroxysmal ( 2 days ) , persistent ( 7 days ) , long - standing persistent and permanent ( 1 year ) . The AF is associated with alterations of the extracellular matrix ( amyloid deposition , inflammatory behaviour , interstitial fibrosis ) , of the myocyte ( apoptosis , hypertrophy , intracellular accumulation of substrate ) , at microvascular level , and with remodelling of the endocardium .

Prolonged hospitalization may be required as the postoperative AF develops in the first three days after heart surgery . The systemic inflammation , triggered by the extracorporeal blood circulation during surgery , and the reactive oxygen species ( ROS ) in the atria are the causes for the postoperative AF .

Monoamine oxidase ( MAO ) is an enzyme on the outer membrane of the mithocondrion in the cardiac cell . It is a major factor in the balance between the reduction and the oxidation reactions in the atrial myocardium . The emission of mitochondrial H2O2 was measured in samples of myocardial tissue from 244 patients for cardiopulmonary bypass . Figure 1 outlines the incidence quartiles of postoperative AF in the cohort based on the enzymatic activity .

Figure 1 . The activity of the MAO and the incidence of the postoperative AF . Copyright ( 2014 ) Journal of The American Heart Association .

There are gaps in the clinical evidence that need to be understood :

Diagnosis

• the increase in the electrocardiogram ( ECG ) screening
• the benefit of multimodal therapy

Epidemiology

• effective biomarkers for antithrombotic therapy
• increase the cohort with undiagnosed AF

Rhythm control

• the atrioventricular node ablation

References :

Anderson E . J . , Efird J . T . , Davies S . W . , O ‘ Neal W . T . , Darden T . M . , Thayne K . A . , Katunga L . A . , Kindell L . C . , Ferguson B . , Anderson C . A . , Chitwood W . R . , Koutlas T . C . , Williams J . M . , Rodriguez E . , Kypson A . P . ( 2014 ) “ Monoamine oxidase is a major determinant of redox balance in human atrial myocardium and is associated with postoperative atrial fibrillation ” , Journal of the American Heart Association , 3 .

Camm A . J . , Kirchhof P . , Lip G . Y . H . , Schotten U . , Savelieva I . , Ernst S . , Van Gelder I . C. , Al – Attar N . , Hindricks G . , Prendergast B . , Heidbuchel H . , Alfieri O . , Angelini A . , Atar D . , Colonna P . , De Caterina R . , De Sutter J . , Goette A . , Gorenek B . , Heldal M . , Hohloser S . H . , Kolh P . , Le Heuzey J . - Y . , Ponikowski P . , Rutten F . H . ( 2010 ) “ Guidelines for the management of atrial fibrillation ” , European Heart Journal , 31 , 2369 - 2429 .

LaPar D . J . , Speir A . M . , Crosby I . K . , Fonner E . , Brown M . , Rich J . B . , Quader M . , Kern J . A . , Kron I . L . , Ailawadi G . ( 2014 ) “ Postoperative atrial fibrillation significantly increases mortality , hospital readmission , and hospital costs ” , The Annals of Thoracic Surgery , 98 ( 2 ) , 527 – 533 .

Key advances in medicine 2014

Nature Reviews published in february 2014 this electronic book free for download on the website .

International experts identified key trends in clinical studies from 2013 . They published 45 articles in 8 medical specialities :

Cardiology

• acute coronary syndromes
• cardiovascular imaging
• dyslipidaemia
• heart failure
• venous thromboembolism

Clinical endocrinology

• adrenal cancer
• metabolism
• puberty
• steroid hormones
• thyroid cancer
• type 2 diabetes mellitus

Clinical oncology

• breast cancer
• cervical cancer
• colorectal cancer
• liver cancer
• lung cancer
• melanoma

Gastroenterology and hepatology

• acute kidney injury
• barrett oesophagus
• cardiovascular disease in chronic kidney disease
• coeliac disease
• faecal microbiota transplantation
• genetics in kidney disease
• hepatitis c
• inflammatory bowel disease
• small bowel endoscopy
• stem cells
• transplantation immunology

Neurology

• dementia
• epilepsy
• movement disorders
• multiple sclerosis
• neuro - oncology
• stroke

Rheumatology

• epigenetics
• gout
• imaging in rheumatology
• systemic lupus erythematosus
• rheumatoid arthritis

Urology

• bladder cancer
• female urology
• kidney cancer
• prostate cancer
• reconstruction
• testicular cancer

Each article has the citation information regarding the original publication . Fine reading !

The recovery heart rate time

It is time for vacation . An idea for doing science , while having a good time , is to study the recovery time of the heart rate . One may have the chance of being an athlete for a day .

The science project that I have in mind requires little effort from the volunteers . A few minutes are needed to fill in information regarding the physical activity . Then an e - mail is received with the location and time when the science project takes place . On the day of the event the person jogs on a park route for a few minutes . The heart rate is measured immediately after the exercise has finished , and after one and two minutes . The event is finished with refreshments .

From the technical point of view , the data is processed based on two equations :

• The maximum heart rate is 220 ( beats per minute ) minus percentage the age of the runner ;
• The target heart rate zone is 50 - 85 % of the maximum heart rate .

The variation with age and gender is analysed for both non - athletes and athletes .

Would you like to participate in this activity , then fill in the form .

The anesthetic for valvular regurgitation

The treatment plans are presented for both the aortic and the mitral valve . The acute and chronic phases are presented . The clinical findings for the functioning mechanism are presented through diagrams .The assessment of the functional capacity , the magnetic resonance images , the electrocardiography , the echo - measurements , and the physical examination are described for the preoperative phase . The presence of infective endocarditis is studied . The anesthetic management is outlined for the clinical environment .

Hydrogels in regenerative medicine

The muscle tissue of the heart is remodelled following the myocardial infarction . The ventricular wall is thinning and the chamber dilates . The adult cardiomyocytes regenerate at a lower rate than the heart requires to function at the required capacity , without any treatment . The clinical strategies are to either use synthetic implants , or to deliver cells directly into the tissue . A solution to avoid their shortcomings is to use hydrophilic hydrogels as a three dimensional structure to deliver cells into the body . The review in Nature presents the hydrogels that demonstrated the ability to enhance vascularisation , or to promote the differentiation of the delivered stem cells .

The mechanical properties of the synthetic hydrogels ( Poly – ethylene glycol , Poly – N – isopropylacrylamide , Poly - 2 – hydroxyethyl methacrylate ) have the ability to control the behaviour of the cells in the damaged area of the myocardium . The NIPAAm - co - AAc - co – HEMAPTMC is a thermosensitive hydrogel that reduces the dimensions of the dilated left ventricle , while implanted in the rat with myocardial infarction . Figure 1 presents the rat myocardium eight weeks after the implantation of the hydrogel . Natural hydrogels ( Matrigel , Fibrin , hydrogel from porcine myocardial extracellular matrix ) increase the cell viability .

Figure 1 . The morphology and the experimental outcomes of the NIPAAm - co - AAc - co – HEMAPTMC thermosensitive hydrogel . ( a ) The composition of the hydrogel . ( b ) The elastic properties of the hydrogel . ( c ) The control experiment with phosphate buffered saline ( PBS ) injection . ( d ) The rat heart after hydrogel injection . ( e ) The histology analysis with hematoxylin / eosin ( H & E ) of the control experiment . ( f ) The H & E histology analysis of the rat cardiac tissue with the injected hydrogel . ( g ) Immunohistochemistry for the tissue grown into the injected hydrogel . Copyright ( 2014 ) Nature Publishing Group .

The hydrogels that demonstrate elastic behaviour while exposed to mechanical cyclic loading have the potential to repair the cardiac tissue . The hybrid of resilin – like polypeptide and Poly – ethylene glycol promotes cell differentiation after seven days of culture . The properties of Methacrylated tropoelastin ( MeTro ) are summarised in figure 2 . The micropatterned surface promotes the alignment and maturation for the cardiac cells , in the day 8 of the experiment. The frequency of the spontaneous beating rates of the cardiomyocytes was measured during two weeks of culture .

Figure 2 . The markers expressed by the primary rat cardiomyocytes . ( a ) The troponin I ( green ) and the nuclei ( blue ) on the surface patterned with The Methacrylated Tropoelastin ( MeTro ) hydrogel . ( b ) The sarcomeric &alpha - actinin ( green ) , the connexin - 43 ( red ) , and the nuclei ( blue ) on the patterned surface . ( c ) Thr troponin I ( green ) and the nuclei ( blue ) on the unpatterned surface . ( d ) The sarcomeric &alpha - actinin ( green ) , the connexin - 43 ( red ) , and the nuclei ( blue ) on the unpatterned surface . ( e ) The beating behaviour of the cardiomyocytes on the unpatterned surface . ( f ) The beating behaviour of the cardiomyocytes on the patterned surface . ( g ) Spontaneous beating rates of cardiomyocytes on the unpatterned surface . Copyright ( 2014 ) Nature Publishing Group .

The conductive hydrogels ( Chitosan , Polypyrrole ) connect areas to propagate the electrical signal into the entire cardiac tissue . The carbon nanotubes in gelatin methacrylate are actuators in the system ( figure 3 ) . The direction of motion varies as a function of the tubular thickness .

Figure 3 . The actuators were designed by incorporating carbon nanotubes ( CNTs ) in gelatin methacrylate ( GelMA) . ( a ) The tightly and the loosely rolled – up constructs were designed . ( b ) The displacement of the beating constructs are a function of frequency and electrical source . ( c ) The linear displacement of a triangular swimmer as a function of time . Copyright ( 2014 ) Nature Publishing Group .

The cardiac progenitor cells , the mesenchymal stem cells , and the pluripotent stem cells have increased potential for differentiation . The stem cell differentiation direction into the cardiac lineage is indicated by the hydrogel matrix in figure 4 . The immunostaining in the 2D hydrogels demonstrates that the sarcomere has diminished length in comparison to the one in the 3D structure .

Figure 4 . The cardiac patch was designed as cardiomyocytes derived from the human embryonic stem cells ( hESCs ) in the hydrogel matrix . ( a ) The result of 2 weeks of in vitro culture . ( b ) The gels microfacricated with elliptical pores . ( c ) The alignment of the hESCs in the hydrogel . The immunostaining on 3D hydrogel of ( d ) troponin T ( red ) , ( e ) myosin heavy chain ( red ) , ( f ) connexin - 43 ( red ) and sarcomeric α – actinin ( green ) . ( g ) The immunostaining on 2D hydrogel of sarcomeric α – actinin ( green ) . Copyright ( 2014 ) Nature Publishing Group .

The growth factors delivered with cells in the hydrogel may increase the efficiency of the process . Figure 5 presents the effect the basic Fibroblast growth factor ( bFGF ) has in a porcine model . The arteriolar density , the left ventricular ejection fraction , and the myocardial perfusion are increased at 4 weeks in culture , when the bFGF is used .

Figure 5 . The influence of the released rate of basic Fibroblast growth factor ( bFGF ) on restoring the cardiac function in a porcine model of the myocardial infarction . ( a ) The presence of the sarcomeric α – actin , ( b ) the arteriolar density , ( c ) the myocardial perfusion , and ( d ) the left ventricular ejection fraction ( LVEF ) were measured under control and the bFGF included conditions . Copyright ( 2014 ) Nature Publishing Group .

Only 10 % of the cells delivered directly in the cardiac tissue survive in vivo . The direct exposure to oxygen , free radicals , and inflammatory cytokines reduces the survival rate of the injected cells . A suitable 3D microenvironment is required . The hydrogel that mimics the cardiac tissue both handles the cyclic loading forces , and maintains the elastic , in addition to conductive , properties . The oxygen – releasing properties of a porous hydrogel , with or without the use of growth factors , increase the control of the system on the cellular environment .

The engineering of complex tissue structures

The laboratory of transplantation biology for regenerative medicine at The University of Gothenburg in Sweden . The research group lead by Professor Suchitra Sumitran – Holgersson designed the first engineered vein succesfully transplanted in the hepatic portal circulation of a 10 - year old female , in 2012 . A donated nine centimeters long iliac vein was used in the study . The cells of the donor were cleared from the three dimensional structure of the vein . The stem cells from the bone marrow of the patient were cultured in the laboratory . The differentiated endothelial and smooth muscle cells grew and divided onto the vessel . There was no need for using immunisuppressives .

Professor Holgersson presented her three future research directions in the talk given at Ted^x in 2012 . Her research team redesiged blood vessels and the trachea , and would continue with complicated organs as the liver and the larynx . Two human organs were thrown away , and Professor Holgersson considered they should be recycled : the placenta as filling material in face cheeks and thighs , and the amniotic membrane for wrapping around areas requiring skin grafts . The animal organ , for example the pig heart , was recycled and redesigned , with the challenging task to meet the in vivo requirements .

References :

Olausson M . , Patil P . B . , Kuna V . K . , Chougule P . , Hernandez N . , Methe K . , Kullberg – Lindh C . , Borg H . , Ejnell H . , Sumitran – Holgersson S . ( 2012 ) “ Transplantation of an allogeneic vein bioengineered with autologous stem cells: a proof - of - concept study ” , The Lancet , 380 ( 9838 ) , 230 – 237 .

Options for mitral valve repair from The Society of Thoracic Surgeons

The quality of patient care is improved with research , and dedication . The Society of Thoracic Surgeons examined in detail the mitral valve surgery at the fiftieth annual meeting , in 2013 . The discussion points were :

• the valve calcification ;
• the mitral regurgitation ;
• low ejection fraction and mitral valve surgery , and atriofibrilation ;
• invasive to minimally invasive surgery, and then surgery with the use of robotic components ;
• methods to increase the repair rates to ninety percent for young surgeons .

Cardiomyocytes for myocardial regeneration

The pumping mechanism of the heart is adjusted by the network of coronary arteries and cardiac veins . Myocardial infarction ocurs when the blood supply is disrupted . In the progressive form , this may lead to heart failure .

The repopulation of the scar is achieved through various methods . One of them is to use autologous bone marrow cells . Another strategy is to differentiate the cardiac progenitor cells ( CPC ) . A third direction is to use cardiomyocytes ( CMs ) derived from human embryonic stem cells ( hESC ) , hESCs cardiac progenitor cells ( hESC - CPC ) , human pluripotent stem cells ( hPSCs ) , or human induced pluripotent stem cells ( hiPSCs ) for the transplantation in the myocardium .

The review paper Concise review : reprogramming strategies for cardiovascular regenerative medicine : from induced pluripotent stem cells to direct reprogramming analyses more than a hundred papers . Three reprogramming strategies for the myocardial regeneration are brought in discussion ( figure 1 ) : the iPSCs technology , the partially reprogramming method and the direct set of approaches .

Figure 1 . The CMs derived from the iPSC ( top ) , the partial reprogramming ( middle ) , and the direct reprogramming technology ( below ) .

The hESCs represent the first reliable source for cardiomyocytes in vitro . The immune rejection , and the patient – or disease – specific hESCs are two challenges for the clinical allogeneic cell transplantation .

The hESCs and hiPSCs may generate beating cardiomyocytes in an inefficient method . The canonical Wnt pathway uses hiPSCs and small molecules in a more efficient signaling strategy .

Cardiomyocytes are partially reprogrammed from the iPSCs through a technology developed in 2006 . It takes a few months to differentiate the colonies of hiPSCs into the cardiac lineage . The use of partially reprogrammed cells reduces the length of time for the process to 11 – 12 days . There are also challenges for reaching the clinical practice ( figure 2 ) . Some of them are : the phenotypic heterogeneity of the differentiating CMs , the tumorigenic risk , and the poor in – vivo survival .

Figure 2 . The phases and challenges of the partially reprogrammed iPSCs method towards clinical practice .

The process of direct reprogramming of fibroblasts into induced cardiomyocyte cells ( iCMs ) is epigenetically stable . It is achieved through various combinations : by adding the Hand2 to the Gata4 , Mef2c and Tbx5 combination of transcription factors ; by using myocardin , and a combination of the Mef2c and Tbx5 transcription factors ; through a combination of a Janus inhibitor and four microRNAs ; by mixing two microRNAs and four transcription factors . The challenges of the myocardial regeneration are reduced through the deliver of reprogramming factors directly to the cardiac tissue .

Progress in the regeneration therapy is achieved if further studies are performed on early stages of myocardial infarction , if the stem cells delivered in – vivo generate efficiently new myocardium , and if the newly developed myocardium has suitable performance for the patient .

Hybrid bioprosthetic heart valve

The peer - reviewed publication Engineering of a bio – functionalized hybrid off – the – shelf heart valve caught my interest . The growth factor signalling mechanism inside the bioprosthetic heart valve is different from the native valve . The Young ' s modulus quantifies the remodeling behaviour after implantation .

The chosen method to generate the scaffold is the electrospinning of either poly - lactide acid ( PLA ) or equal amounts of it and poly - ethylene glycol dimethacrylate ( PEGdma ) . The performance of the polymeric scaffold is tested under physiological conditions . The blood is assumed to interact with the heart valve leaflet at large amplitude , in a laminar flow , under oscillatory shear stress . The nonlinear flow properties affect the response of the heart valve .

Valvular endothelial and interstitial cells are seeded in the scaffold . The protein configuration is visualised on the cell – seeded polymeric scaffolds using immunofluorescence staining . The cell viability is assessed with 3 - ( 4 , 5 - dimethyl – 2 - thiazolyl ) - 2 , 5 - diphenyl - 2 H - tetrazolium bromide ( MTT assay ) . The cells are compatible with both the PLA and the PEGdma – PLA scaffold . The valvular endothelial cells adhere in a greater amount onto the PEGdma – PLA scaffold than on the one with PLA fibres . The valvular interstitial cells adhere similarly on both polymeric scaffolds . The valvular actin cytoskeleton for both the endothelian and the interstitial cells is more visible in the PEGdma – PLA than in the plain PLA scaffold .

Native porcine aortic valve tissue , unseeded and cell – seeded polymeric scaffolds are analysed using the scanning electron microscopy ( SEM ) . The PLA scaffold has 30 times greater fibre diameter and 1160 times greater pore size than the native leaflet .

The atomic composition of the surfaces is determined using the electron spectroscopy for chemical analysis ( ESCA ) . The comparison of the data is made using literature values for single components . The PLA – PEGdma scaffold has both PLA and PEGdma groups on the analysed surface .

The mechanical properties of both native and polymeric scaffolds are using the atomic force microscopy ( AFM ) . The spongiosa is the softest layer of the native porcine leaflet , with a Young ' s modulus twice as small as the one for the ventricularis and fibrosa layer . The Young ' s modulus of the PLA – PEGdma scaffold is 10 times greater than the ventricularis and fibrosa native layer .

Uniaxial tensile testing provides information regarding the Young ' s modulus , the tensile strength and the elongation values . Both the PLA scaffold and the native leaflet is soft , with similar values for the Young ' s modulus . The computed Young ' s modulus for the PLA – PEGdma scaffold is twice the value for the PLA scaffold . The PLA scaffold is 55 times more expansible than the native leaflet . The tensile strength value is similar for both the PLA and PLA – PEGdma scaffold .

The polarity of the molecules on the surface is detected using the contact angle goniometry technique . The PLA scaffold is highly hydrophobic . The PEGdma scaffold is hydrophilic . The PLA – PEGdma scaffold is highly hydrophilic . The PLA – PEGdma is highly hydrophilic .

The capacity of water - holding of both the native and the polymeric scaffolds is compared . The PLA scaffold has 11 % water intake capacity , the PEGdma scaffold has high value , while the native leaflet has 90 % . The PLA – PEGdma scaffold has 5 times more water intake capacity than the PLA scaffold .

The protein expression patterns are revealed in the early development for the human heart tissue . Collagen type 1 is present in the leaflets , Versican in the atria – ventricular valves and in the outflow tract , in the first trimester of the fetal development . Collagen type 1 is present in the fibrosa layer of the aortic valve , Versican in the leaflet tip and close to the arterial wall , in the second semester of the fetal development . The valvular histoarchitecture in the 19 years old adolescent is similar to the one in the second semester of the fetal development .

The bio – functionalised prosthetic leaflet has PLA – PEGdma scaffold , Collagen type 1 gel layer , and Versican tip , in a proof – of – principle experiment . The polymeric scaffold requires further structural modifications to have a biocompatible material with a set of mechanical properties closer to the one of the human heart valve .

References :

Hinderer S . , Seifert J . , Votteler M . , Shen N . , Rheinlaender J . , Schaffer T . E . , Schenke – Layland K . ( 2014 ) “ Engineering of a bio – functionalized hybrid off – the – shelf heart valve ” , Biomaterials , 35 ( 7 ) , 2130 – 2139 .

Hyun K . , Wilhelm M . , Klein C . O . , Cho K . S . , Nam J . G . , Ahn H. , Lee S . J . , Ewoldt R . H . , McKinley G . H . ( 2011 ) “ Progress in Polymer Science ” , 36 ( 12 ) , 1697 – 1753 .