**2. Biomaterials and RP techniques in thousands of postures**

prototyping (RP) technology is extraordinarily needed. A biomaterial is defined as any mat‐ ter, surface, or construct that interacts with biological systems [12]. It may be an autograft, allograft or xenograft transplant material, or a nature derived or laboratory synthesized chemical component. Biomaterials are often used and/or adapted for a medical application, and thus comprise whole or part of a living structure or biomedical device which performs, augments, or replaces a natural function [13]. RP, also referred to as additive manufacturing (AM) or solid freeform fabrication (SFF), is a set of manufacturing processes which can de‐ posit materials layer-by-layer until a CAD model with freeform geometry has been built. RP technology, which has been widely used in the automatic fabrication of complex geometric structure areas, carries the promise to become the most convenient and reliable technique

Over the last two decades, tissue-engineering researchers have devoted themselves to seed‐ ing cells onto a porous biodegradable scaffold material to direct cell differentiation and functional assembly into three-dimensional (3D) tissues [19]. This strategy has achieved a great success in simple tissue/organ regeneration [20]. However, it is extremely difficult for this strategy to be used in creating a branched vascular system or a complex organ regenera‐ tive template mimicking the native ones with similar mechanical and biological properties. Similar to building a nuclear power plant for complex organ manufacturing, there is a sig‐ nificant gap between simple tissue/organ engineering and complex organ manufacturing approaches both in fabrication technique employed and ultimate goal achieved (Table 1)

**Complex organ manufacturing Nuclear power plant building**

Cells Bricks, nuclear reactors

Vascular systems Water and light pipes Nerve system Electric control system

**Table 1.** Analogues between complex organ manufacturing and nuclear power plant building.

ed; meanwhile the future development directions have been highlighted.

The ultimate goal of complex organ manufacturing is to fabricate hybrid biomaterial (in‐ cluding living cells, even gene/protein) structures over a range of size scales (i.e. from a few micrometers to a few millimeters). We herein provide insights into some special integrations of biomaterials and RP techniques towards the purpose of intelligent freeform manufactur‐ ing of complex organs. The most successful and promising integrations have been highlight‐

Synthetic, natural polymers Steel Crosslinking agents Cements

Multi-nozzle rapid prototyping machines Cranes CAD models Blueprints Construction Architecture

for manufacturing of complex organs in the coming years [14-18].

438 Advances in Biomaterials Science and Biomedical Applications

[14-18].

As stated above, biomaterials, usually acting as synthetic frameworks (referred as scaffolds, matrices, or constructs), can be categorized into different groups according to their supply sources, existence states, chemical properties as well as biomedical applications. Typically, patient specific blood, cells (especially stem cells), acellular matrices, tissues and organs are a kind of biomaterials with no immune reactions. More than 100 implantable biomaterials have been reported in different forms, such as bulks, blocks, membranes, sheets, beads, hy‐ drogels, fibers, sutures, plates, nets, meshs, tubes, non-woven fabrics, porous scaffolds (or sponges), heart valves, intraocular lenses, dental implants, pacemakers, biosensors, etc [21-23]. However, very few of them are suitable for complex organ manufacturing purposes. For biomedical applications, biocompatibility, biodegradability and processing ability are among the most crucial issues one should consider. In most cases the implantable biomateri‐ al has to be nontoxic, biocompatible, and biodegradable. Therefore, stringent criteria must be met before proceeding to clinical applications.

Especially, hydrogels are a family of natural or synthetic polymers with high water contents. During the last twenty years, hydrogels have been an important class of soft tissue repair materials or cell delivering vehicles that can be fabricated in the form of 3D micro-periodic structures by colloidal templating [24], interference lithography [25], direct-writing [26], inkjet printing [27], and two-photon polymerization (2PP) [28].

In the last four decades, significant advances have been made in the progress of scaffold fab‐ rication techniques for biomedical applications. For example, synthetic and natural biode‐ gradable polymers, such as polylactic acid (PLA) [29], poly(lactic/glycolic) acid (PLGA) [30], collagen [31], hyaluronic acid [32] and chitosan [33], are often used as pure implantable bio‐ materials or tissue engineering scaffolds.

In parallel with the development of biomaterials, the number of commercial RP techniques has expanded rapidly during the last decade. More than 30 different RP techniques have been applied in the most diverse industries. Several companies are now using RP technolo‐ gies for plastic, wood and metal product manufacturing. For example, Siemens, Phonak Wi‐ dex, and other hearing aid manufactures use selective laser sintering (SLS) techniques to produce hearing aid shells. Align technology uses SLS techniques to fabricate molds for pro‐ ducing clear braces ("aligners"). And Boeing and its suppliers use SLS techniques to pro‐ duce ducts and similar parts for F-18 fighter jets [34]. Around 20 of the RP techniques have been adapted in the field of regenerative medicine [35]. Basically, these adaptations can be classified into three major groups hinged on the RP working principles (Figure 1): (i) nozzlebased extruding/assembling/deposition systems, e.g. fused deposition modeling (FDM) (Fig‐ ure 1A) [36], pressure assisted manufacturing (PAM), low-temperature deposition manufacturing (LDM), and bio-plotters (3DB) (Figure 1B) [37,38], which deposit materials either thermally or chemically through pens/syringes/nozzles; (ii) laser/photolithographybased writing systems, e.g. laser-guided direct writing, which arrange meterials/cells by la‐ ser beams [39,40] or photopolymerize a liquid (resin, powder, or wax) in stereolithography (SLA or STL) (Figure 1C) [36,41], or sinter powdered material in SLS systems (Figure 1D) [42]; (iii) printing-based inkjeting systems, e.g. 3D printing (3DP) systems and wax-based systems, which print a chemical binder onto a powder bed and print two types of wax mate‐ rials in sequence (Figure 1 E) [36].

The Integrations of Biomaterials and Rapid Prototyping Techniques for Intelligent Manufacturing of Complex Organs http://dx.doi.org/10.5772/53114 441

[42]; (iii) printing-based inkjeting systems, e.g. 3D printing (3DP) systems and wax-based systems, which print a chemical binder onto a powder bed and print two types of wax mate‐

rials in sequence (Figure 1 E) [36].

440 Advances in Biomaterials Science and Biomedical Applications

**Figure 1.** Working principles of various rapid prototyping systems: A) Schematic illustration of the nozzle-based FDM process [36]. B) Scheme of a nozzle-based 3D-Bioplotter heated cartridge setup [37,38]. C) Schematic of the laserbased SLS techniques [36]. D) Schemes of two laser-based of stereolithography (SLA or STL) setups [39]. Upper: a bot‐ tom-up system whereby the laser scans the surface for the curing of the photosensitive materials. Bottom: a top-down setup with dynamic digital light projection to cure a complete 2D layer at once. E) Schematic of the 3DP systems [36].

Although most of the adapted techniques can be used in building complex geometrical shapes with CAD modelling, every technique group is subjected to a limited biomaterial incorpora‐ tion ability and has its own drawbacks in creating 3D living organs. For example, Chu and coworkers have developed design-for-manufacturing rules for their lattice mesostructure fab‐ rication technique with a STL system. Lattice structures tend to have geometry variations in three dimensions [43]. However, this system is not fully capable of creating a branched vascu‐ lar system, which is vitally important in the context of organ manufacturing to direct spatially heterogeneous tissue development. On the other hand, Arcaute and coworkers have encapsu‐ lated human dermal fibroblasts in a synthetic poly(ethylene glycol)-dimethacrylate hydrogel by a SLA technique. Without porous structures and biodegradable properties of the synthetic polymers, it is hard for the cells to form tissues inside the hydrogel [44]. The integrations of bi‐ omaterials and RP techniques can form a huge "family tree" with many different combina‐ tions. Figure 2 summarizes the integrations of biomaterials with RP techniques and their potential usages in complex organ manufacturing.

Currently, as the concepts of "factory in a box" and "desktop manufacturing" are expand‐ ing, new applications of RP techniques in architectural design and 3D construct building in‐ crease speedily. Among the most popular RP techniques, the Fab@Home equipments with an average price of about 3000 US dollars are among the most convenient and cost effective RP instruments used in biomaterial fabrication field [45].

**Figure 2.** A "family tree" indicates various integrations of biomaterials and rapid prototyping techniques.

At present, the concepts of "scaffolds", "tissues", and "organs" are rather confused both in scientific and industrial areas. Most researchers and manufacturers in the area of tissue engi‐ neering like to label their RP products as "scaffolds", "tissues", or "organs". It is reasonable to describe an accellular porous 3D structure with a micro-scale internal architecture but without cells as a "scaffold". However, those with living cells incorporated should be de‐ fined as "constructs". Especially, those with cells have already connected to each other to perform special functions should be called "tissues". As described in the beginning of the introduction section, those with more than three different tissue types inside a construct should be called "organs". Simple organs, such as the bladder and blood vessels, should have less than or equal to three tissue types, while complex organs, such as the liver, heart, and kidney, should posses more than three tissue types. With these definitions, it is easier to distinguish which RP technique will be useful in complex organ manufacturing.
