# Whole Organ Engineering: Approaches, Challenges, and Future Directions
## 4 Approaches to Engineering Whole Organs
### Building Organs from Biohybrid Materials  
Biohybrid materials are materials comprising both biological and non-biological components. Biohybrid materials have been explored in tissue engineering applications due to certain drawbacks of tissue scaffolds comprised solely of biological components. For instance, the ECM plays a vital role in directing native cell activity and ECM-derived proteins have demonstrated the same ability in engineered constructs [26; 27]. However, objects made of only ECM proteins can rapidly degrade or are not structurally robust enough to replicate the activity of compliant, matrix-dense tissues [72]. Synthetic polymers can be tuned on the molecular level to generate a scaffold with desired bulk properties to mimic native ECM's mechanical properties [72]. Pairing the cellularly interactive ECM proteins with the mechanical and degradation tunability of synthetic polymers can produce biocompatible scaffolds that can be modified to suit remodeling of different tissue types. There are four types of commonly used biohybrid materials: (1) interwoven biological and non-biological fibers, (2) bilayers comprising distinct synthetic and ECM layers, (3) synthetic scaffolds seeded with cells that synthesize ECM in the scaffold, and (4) composite hydrogels. Interwoven synthetic and biological fibers are often formed using electrospinning, and electrospun biohybrid scaffolds have been implemented in engineering vascular grafts [73; 74; 75; 72]. Co-spinning synthetic and biological polymers allows for the production of independent and distinct fibers on the nanoscale,though the deposition of the fibers can be difficult to control and produce a random fiber orientation [76]. Fiber diameter can be modulated by controlling speed and charge of material deposition and can be adjusted to resemble native ECM both in its dimensions and structural properties [75; 76]. Electrospun biohybrid scaffolds can also be designed with an adequately porous structure to allow for high cell infiltration and migration [75; 76]. In biohybrid bilayers, the synthetic and biological components are discrete components that are combined in layers [72]. Because the two materials are distinct constituents, generally, a biohybrid bilayer takes advantage of the properties of a primary material and uses a secondary material to provide support; for example, the primary material may be the synthetic layer to provide mechanical strength while the secondary biological layer provides key cell interactive cues [72; 77]. Some bilayer materials utilize intact native tissue, such as the pericardium, due to its high ECM protein content, low cellularity, and mechanical properties, with a synthetic polymer layer surface crosslinked to the pericardium [78]. Three-dimensional printing is also a suitable bilayer manufacturing technique, as layer-by-layer fabrication is readily performed with a 3D printer [79]. For biohybrid materials in which the ECM component is produced by cells seeded on a synthetic polymer scaffold, the successful integration of ECM proteins depends on the ability of the synthetic component to allow high cell infiltration and promote cellular production of ECM [72]. Because these materials incorporate cells, decellularization of the material after adequate ECM synthesis is a critical step [72]. This type of biohybrid material may be particularly suitable for tissue-specific use if the cells used to fabricate the ECM in the scaffold can be sourced from the tissue site of interest, as the ECM produced by these cells will have the same composition as the native ECM [72]. Hydrogel blends are formed by combining ECM proteins and synthetic polymers prior to gelling the two to form a single, composite hydrogel. Polyethylene glycol (PEG) is often incorporated into biohybrid hydrogels due to its bioinert property, well understood tunable degradation mechanics, and high solubility in water [80].