Table 1.

Advantages and disadvantages of natural materials used for cardiac tissue engineering.

Material	Advantages	Disadvantages
EHT	• Can be easily shaped or cast to the complex geometry of the myocardium, and so can provide efficient bonding to the native tissue • Good electrical coupling is possible • Can be generated easily with minimal variation • Have similar characteristics to heart tissue, meaning that they are suitable for drug toxicology • CRISPR/Cas9 can be used in conjunction with pluripotent stem cells and EHTs to generate tissues with patient specific diseases • Can be fused together to create relatively large constructs	• A true adult cardiomyocyte phenotype has not been reproduced • Larger EHTs with sufficient cells for clinical relevance have not yet been produced • As of yet EHT viability is not maintained as vascularization is unable to reach the core of the grafts • A fibrotic interface is often seen between the myocardium and EHT and this can reduce the chance of definitive electrical coupling
Collagen	• It is inherently biocompatible, superior to that of many other natural polymers • It is inherently bioactive due to the presence of appropriate binding ligands for cardiac cell attachment • It has modifiable biodegradability • It has low antigenicity • Collagen scaffolds are versatile, with many relevant physical, chemical, mechanical, and morphological properties being tailorable to achieve specific functions • Collagen can be extracted in large quantity from a wide range of tissue sources at high purity, and at relatively low cost • It has an abundance of potential ligand sites to promote cellular activity during myocardial tissue regeneration • Collagen, in particular fibrillar type I, is the main constituent of the ECM of many hard and soft tissues • It supports myocyte alignment and contributes to matrix resistance to deformation during the cardiac cycle, playing an important role in the maintenance of myocardium shape, thickness, and stiffness	• The low stiffness of gel-like systems and poor ability to create a spatial bio-mimetic environment somewhat limits its in vivo applications • There is difficulty in designing collagen scaffolds that have nonlinear elasticity similar to the heart muscle and therefore it is difficult to develop a scaffold which beats synchronously with the recipient heart • There is an unmet need for vascularization which is crucial for adequate mass transport, cell survival, electromechanical integration and functional efficiency of the transplanted cardiac patch
Alginate	• Alginates are natural polysaccharides that are considered to be biocompatible, biodegradable, non-toxic, and non-immunogenic • The scope of the applications of alginates in the field of biomedicine is broad, including cell transplantation, drug, and protein delivery, and wound healing • It has a non-thrombogenic nature • Can be directly and locally injected into the infarcted myocardium or via intracoronary injection and therefore it's use doesn't require open surgery	• Mammals lack the alginase enzyme, therefore alginate is a non-degradable material, however, the partial oxidation of alginate chains promotes degradation under physiological conditions • Alginate hydrogels have poor bioresorbability and low cell adhesiveness, which may lead to adverse tissue interaction and poor wound-healing properties
PHAs	• Many polymers in the PHA family are highly flexible elastomers which make them ideal for soft tissue engineering • PHA derived tissue engineering scaffolds have the potential to maintain their structural integrity over a longer period due to surface degradation vs. bulk degradation observed in PLA and PLGA • They are highly biocompatible and bioresorbable • They have diverse mechanical properties • PHAs can be used for different aspects of cardiac tissue engineering such as patches, and valves • PHA based sutures are FDA approved • Other commercial products include mesh constructs for ventral and inguinal hernia repair; patches for tendon and ligament repair; mesh constructs for face and breast lifts • Can be processed to make a diverse range of materials, including 3D printed bespoke structures, electrospun (solution and melt) fiber sheets, gyrospun fiber sheets, porous 3D scaffolds, melt extruded and dip molded tubular structures, solvent cast films, hydrogels, microspheres, and nanospheres • PHAs are sustainable polymers produced using fermentation and do not need to be isolated from animal/human tissue	• The medical grade PHA production method is mostly quite expensive and not many commercial sources are available • Often, different PHAs require blending together in order to produce a material with suitable mechanical properties for cardiac applications • Some PHAs are susceptible to thermal degradation
Silk	• A variety of silk-based biomaterials have been approved by the FDA • Good adherence to native cardiac tissue • Cause little to no immunological response • Silk-based biomaterials have diverse tuneability • Its high elasticity makes silk a good biomaterial for cardiac applications as it has the mechanical properties to cope with the constant contraction and relaxation of the muscle • It has been shown to have good cell adhesion • Can be used to make a diverse range of structures, including fibers, foams, hydrogels, nanoparticles, films, and 3D printed structures • It is bioresorbable	• Silk usually has to be combined with other materials to make it suitable for cardiac applications • The natural production of silk by spiders leads to batch-to-batch variability due to different species and even within individual spiders
Chitin/chitosan	• They are biocompatible (287) • Can be processed into films, membranes (288), hydrogels, fibers, scaffolds, and sponges (289) • Chitin and chitosan gels can be used for drug delivery (290) • Chitin has an adhesive nature (289) which can be useful in applications such as myocardial patches • Chitin also has bactericidal and antifungal characteristics, which can reduce the risk of infection if used in an application that requires implantation (289)	• Chitin has a rigid crystalline structure, making it difficult to dissolve in common solvents (288) • Chitin and chitosan are derived from individual organisms (e.g., crustaceans, insects, fungi) (287) leading to batch-to-batch variability
Decellularized heart	• It is biocompatible as it is derived from animal or human donors • Can be used to make both myocardial patches and cardiac valve replacements (291) • This has a pre-existing structure; therefore, this material requires less processing	• Decellularized heart can't be processed into as many different forms as other natural materials • It cannot be degraded after implantation • If any cells remain after decellularization of a xeno- or homograft, this can elicit an immunogenic response once implanted (291)
Omentum	• Part of a patient's own omentum can be removed by a minimally invasive procedure (292) • It is biocompatible as it is usually taken from the patient being treated • Omentum-based hydrogels can be made and used to encapsulate cells (293) • Omentum can be made into a myocardial patch (294)	• Where used to make an implanted myocardial patch, two surgeries are required—one to harvest the omentum and one to implant the patch. Surgery comes with risks, especially for a patient with a heart condition