Collagen and Elastin Biomaterials for the Fabrication of Engineered

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Collagen and Elastin Biomaterials for the Fabrication of Engineered Living Tissues David Miranda-Nieves, and Elliot L. Chaikof ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.6b00250 • Publication Date (Web): 11 Jul 2016 Downloaded from http://pubs.acs.org on July 14, 2016

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ACS Biomaterials Science & Engineering

Collagen and Elastin Biomaterials for the Fabrication of Engineered Living Tissues David Miranda-Nieves ⌘,§ and Elliot L. Chaikof *,§,¶ ⌘

Department of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA

§

Department of Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA

¶

Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02215, USA⌘

ABSTRACT Collagen and elastin represent the two most predominant proteins in the body, and are responsible for modulating important biological and mechanical properties. Thus, the focus of this review article is the use of collagen and elastin as biomaterials for the fabrication of living tissues. Considering the importance of both biomaterials, we first propose the notion that many tissues in the human body represent a reinforced composite of collagen and elastin. In the rest of the article, collagen and elastin biosynthesis and biophysics, as well as molecular sources and biomaterial fabrication methodologies, including casting, fiber spinning, and bioprinting, are discussed. Finally, we summarize current attempts to fabricate a subset of living tissues, and, based on biochemical and biomechanical considerations, suggest that future tissue-engineering efforts consider direct incorporation of collagen and elastin biomaterials.

KEYWORDS: collagen, elastin, biomaterials, tissue engineering, skin, blood vessels, cartilage, liver

1. INTRODUCTION Collagen and elastin biomaterials offer the promise to revolutionize the way we engineer living tissue. Tissues in the body consist of two main components, cells and extracellular matrix (ECM). In broad terms, the latter consists of a series of macromolecules, including proteins and carbohydrates, which dictate the biological and mechanical behavior of tissues. Collagen is the most predominant of these ECM proteins, constituting up to 30% of the dry weight of the body1,2. This protein provides structural support and strength, and mediates local biological responses. Elastin is the second most common structural component in the ECM, responsible for contributing the elasticity and characteristic resilience of many living tissues3,4.

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Despite differences in function and location, tissues including skin, blood vessels, tendon, ligaments, and elastic cartilage share collagen and elastin as common protein constituents (Figure 1). In fact, the body is in many respects a reinforced composite of collagen and elastin, and efforts to engineer living tissues should incorporate biomaterials based on both collagen and elastin.

Figure 1. Verhoeff-van Gieson stain of images of (A) human aorta [20x], (B) human skin [20x], and (C) human elastic cartilage [270x]. Elastin fibers stain black and collagen fibers. (D) Hematoxylin and eosin staining of human tendon [100x]. Collagen fibers stain pale and nuclei blue. Adapted with permission from references (A, B) 5, (C) 6, and (D) 7.

This review evaluates these two proteins as biomaterials, beginning with an explanation of their most basic properties, including their biosynthesis and biophysical features.

We review molecular extraction and

purification methodologies of collagen and elastin from various sources; the most common modalities used to fabricate biomaterials from these proteins; and finally, current efforts that utilize collagen and elastin biomaterials to engineer living constructs including liver, skin, and cardiovascular and musculoskeletal tissues.

2. BIOSYNTHESIS 2.1. Collagen Biosynthesis. Collagen, the most abundant macromolecule in the ECM, is a triple helical protein that consists of three chains with a characteristic repeating sequence (Gly-X-Y)n; where the X and Y position are often occupied by proline and hydroxyproline8,9. To date, 28 genetically different types of collagen molecules have been identified10,11.

However, the most common are those categorized as fibril-forming

collagens. These collagens (type I, II, III, V and XI) possess the ability to assemble into highly oriented fibers


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with diameters that range between 25 and 400 nm and have a characteristic banding pattern with a periodicity of approximately 70 nm, known as d-periodicity (Figure 2)12.

Figure 2. (A) Schematic representation of supramolecular assembly of collagen fibrils. The monomers are 300 nm long, with characteristic d-periodicity. (B) Collagen type I fibrils as they arranged in tendon. (C) Collagen type II fibrils in articular cartilage. Reprinted with permission from reference 9.

Fibroblasts are responsible for producing the majority of the collagen in the body, although other cells share this capacity13.

Collagen production beings in the nucleus with transcription of DNA into mRNA.

Approximately 45 genes have been discovered to code for mRNA sequences, which depending on the collagen type can vary between 3 to 117 exons14.

Propeptide molecules are synthesized in the rough

endoplasmic reticulum through translation of mRNA and then travel to the Golgi apparatus. Post-translation, the molecules are glycosylated and proline is hydroxylated by prolyl-hydroxylase enzymes and cofactors, including ferrous ions, molecular oxygen and ascorbate15. The presence of hydroxyproline allows for the formation of intramolecular hydrogen bonds, which contribute to the stability of the triple helix, and later the integrity of the collagen fibrils16. Procollagen is self-assembled into α-chains (triple helical structure) inside the Golgi apparatus and secreted as ECM. Outside the cell, C and N-propeptides are cleaved allowing for the spontaneous aggregation of tropocollagens into fibrillar structures, an entropic-driven process that occurs through the disruption of ordered solvent molecules17. Finally, covalent and non-covalent interactions form ACS Paragon Plus Environment


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between the tropocollagen molecules resulting in the formation of collagen fibers with diameters of 10-300 nm13. 2.2. Elastin Biosynthesis.

Elastin is an insoluble biopolymer with limited turnover in healthy tissues,

estimated to have a half-life of 70 years18. Elastogenesis, which can be modulated by various cells, including smooth muscle cells (SMC), fibroblasts, endothelial cells (EC), chondroblasts, and mesothelial cells, occurs primarily during late fetal and early neonatal periods19,20. During adult life, synthesis only occurs if elastic fibers are subject to injury21. Tropoelastin (TE), the precursor of crosslinked elastin, is a water-soluble molecule with a molecular weight of approximately 72 kDa that alternates non-polar hydrophobic and hydrophilic domains22,23. TE is translated on the surface of the rough endoplasmic reticulum from mRNA sequences of approximately 3.5 kb, which have undergone significant post-transcription splicing24.

Once translated, TE travels to the Golgi apparatus,

chaperoned by a 67k Da elastin-binding protein (EBP) that prevents intracellular aggregation and premature degradation25. The Golgi apparatus secretes the TE-EBP complex to the ECM, where it interacts with aligned microfibrillar scaffolds that orders the tropoelastin monomers for subsequent elastic fiber formation (Figure 3)26.

Figure 3. Elastogenesis. (A) TE-BMP complexes are secreted to the ECM. (B) TE coacervates, interacts with aligned microfibrillar scaffold, and is crosslinked by lysyl oxidases. (C) Elastin fibers are formed. Diagram is not drawn to scale. Adapted with permission from reference 3.

To facilitate crosslinking, TE molecules associate through an entropically-driven process known as coacervation27.

Coacervation refers to an inverse temperature transition that causes TE molecules to

aggregate with increased temperature.

While these molecules are soluble at low temperatures, they

aggregate and order at higher temperatures, due to interactions between hydrophobic domains. ACS Paragon Plus Environment

At low

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temperatures water molecules form a clathrate-like structure around the entire TE molecule, maintaining the protein in an unfolded state. However, upon raising the temperature, the system’s overall entropy increases through the disruption of water, allowing the hydrophobic domains to fold and interact28,29. This process is finely tuned to the physiological conditions of the body (37˚C, 150 mM NaCl, pH 7-8). Once aggregated, the TE molecules are crosslinked through the action of the copper-dependent lysyl oxidase25.

3. BIOLOGICAL AND MECHANICAL PROPERTIES 3.1. Properties of Collagen. Being the major macromolecule in the ECM, collagen plays a crucial role in cell behavior and biomechanics. Specific cellular receptors, for example integrins, receptor tyrosine kinases and proteoglycan receptors mediate cellular interactions such as adhesion, growth, or differentiation30. Recent studies in mechano-transduction have demonstrated the role of collagen, among other molecules, in transducing forces from tissues to cells, as well as its effects in modulating cellular phenotype and function31. Further, collagen has been shown to contribute to the local storage and release of growth factors and cytokines during wound healing and tissue repair processes1,32. The biomechanics of collagen molecules have been well characterized33,34. The Young’s modulus has been calculated to be approximately 4 GPa, with an elastic behavior in an elongation range of 2.5-4%3,35. Molecular dynamics, as well as optical tweezers have revealed that for small deformation the mechanics are controlled by entropic elasticity caused by molecular ordering, while at larger deformations it transitions to energetic elasticity8,36.

This transition is caused by the stretching and breaking of intramolecular bonds, including

hydrogen bonds, as well as the deformation of covalent bonds in the protein backbone. These models have predicted a persistence length of 16 nm, which suggests that collagen molecules are flexible elastic entities that exhibit worm-like chain behavior under mechanical forces below 14 pN8,36. 3.2. Properties of Elastin. Elastin is the second most abundant macromolecule in the ECM; and thus, is an important regulator of cell behavior and tissue biomechanics. Macroscopically, crosslinked elastin appears as a pale-yellow amorphous mass. However, electron microscopy reveals a fibrillar structure of parallel 5 nm thick filaments37. The water content of elastin varies depending on temperature. In a study by Gosline, purified bovine ligamentum nuchae contained 0.46 grams water per gram of protein at 37°C, which increased to 0.76 at 2°C38. Among its various biological properties, elastin-derived peptides regulate skin fibroblast ACS Paragon Plus Environment


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proliferation39, aortic rings vasodilation40, SMC migratory inhibition41, endothelium-dependent vasodilation42, and SMC proliferation43. For example, Indik et al. demonstrated that elastin-rich matrices attracted more SMCs and ECs than surfaces coated with other biomaterials44. The Young’s Modulus of elastic fibers ranges between 300 and 600 kPa, with a maximum extension of 100– 220%3,4,45. However, the most important property of the elastin molecule is that it can withstand billions of cycles of extension and recoil without failing46. Over the years, various models have been developed to explain the biomechanics of elastin3. The random chain model suggests that elastin behaves like a classical rubber, in which the polymers are kinetically free and exist in a high entropic state47. Stretching orders the chains and limits the overall entropy of the system, which provides the restoring force for recoil48. On the other hand, the liquid drop model suggests that enthalpic forces govern recoil. When the protein is stretched its chains are deformed, exposing the hydrophobic side chains of tropoelastin, and thus increasing the overall energy in the system, which is then released through recoil49. Lastly, the fibrillar model proposes that elasticity arises from second-order configurations. Circular dichroism (CD) analysis of recombinant human tropoelastin revealed the presence of α-helices (3%), β-sheets (41%), β-turns (21%) and other structures50. The significant presence of β-turns in the structure of the protein suggests that any deformation that further bends this structure increases the energy of the system and gives rise to recoil.

4. MOLECULAR SOURCES 4.1. Collagen Sources. Considering the importance of collagen in engineering tissues, researchers have explored various methods to purify or synthesize collagen-based molecules. In this section, we will review extraction and purification from animal sources, as well as advances in the development of recombinant collagen. 4.1.1. Animal-derived collagen. Collagen, particularly type I collagen, can be extracted and purified from various animal sources in large quantities, including porcine skin, bovine tendon, rat tail, or marine sources (Figure 4)51,52. Although mature collagen fibrils contain chemical crosslinks, which limit their dissolution in water, collagen can be obtained from tissues of younger mammals53,54.

The most common methods for

extraction include the use of neutral salt solution (0.15 - 2 M NaCl), dilute acetic acid (0.5 M), hydrochloric acid


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(pH 2-3), and alkali and enzyme treatment55–57. Soluble collagen can then be purified by precipitation after pH, salt concentration, or temperature adjustments. 4.1.2. Recombinant collagen.

The major drawbacks of animal-derived collagen include batch-to-batch

variability, the requirement of good manufacturing practices (GMP) to eliminate potential contamination of pathogens, and moral and ethical-biases associated with harvesting tissues from animals4,51. For this reason, investigators have explored recombinant systems and polymer synthesis as alternative sources of collagen molecules (Figure 4)58–63.

Although recombinant human collagen (rhCol) has been expressed in various

platforms, such as yeast, E. coli, mammalian cells, insect cells, tobacco plant and corn seeds, the biggest challenge has been mimicking the post-translation modification of proline hydroxylation64–67. Nonetheless, addition of prolyl 4-hydroxylase (P4H) coding domains to recombinant sequences has proven successful in hydroxylating rhCol68–70. Despite the advantages of rhCol, including control over amino acid sequence, chain length, and addition of crosslinking groups71,72, applications have been limited due to the high cost of protein expression63,73.

Figure 4. Molecular sources of collagen including animal and recombinant sources.

4.2. Elastin Sources. Considering the importance of elastin in tissues, a number of strategies have been pursued to synthesize or extract elastin-based molecules, including extraction and purification from animal sources, recombinant expression of tropoelastin, and the engineering of elastin-like peptides. 4.2.1. Animal-derived elastin. Despite being an insoluble protein after crosslinking, elastin can be obtained from various animal sources through partial hydrolysis of the peptide chain74. Agents used for hydrolysis ACS Paragon Plus Environment


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include hot alkali, guanidine, oxalic acid and potassium hydroxide22,75. Although each method yields different versions of soluble elastin, all protocols have a similar framework. Protocols begin with animal tissues rich in elastin, such as bovine ligamentum nuchae; other macromolecules are removed, including collagen, glycosaminoglycans, and carbohydrates; and elastin is fragmented by cleaving peptide bonds76,77. These fragmented peptides possess properties similar to tropoelastin, such as the capacity to coacervate78. However, purification from animal sources results in a heterogeneous mixture of partially crosslinked elastin peptides, with compromised biological properties79. Further, depending on the protocol, the final product can show evidence of degradation and contain high levels of contaminants80. 4.2.2. Animal-derived tropoelastin.

Considering that elastin is made up of crosslinked tropoelastin

monomers, a number of approaches have been explored to produce TE81. Tropoelastin can be derived from animal sources at late fetal or neonatal stage, before it is crosslinked into elastin by feeding newly born animals a diet deficient in copper, a critical cofactor in lysyl oxidase activity23,82. Nonetheless, the presence of uncrosslinked lysine residues renders extracted TE more susceptible to degradation by trypsin-like proteases, as well as an overall positive charge80. Further, the molecular weight of extracted TE is often heterogeneous. 4.2.3. Recombinant tropoelastin. Due to ethical considerations associated with animal sources, a number of recombinant human tropoelastin (rhTE) products have been produced. The first attempt to express rhTE dates to 1990 when Indik et al. expressed rhTE in E. coli using vectors containing cDNA sequences similar to the gene that codes for human TE83. The recombinant product was confirmed by evaluating cross-reactivity with antibodies directed at mixtures of derived human tropoelastin. Weiss has significantly improved the yield of rhTE and has since used rhTE as a model to study the behavior of human elastin and fabricated tropoelastinbased biomaterials for various tissue-engineering applications84–89.

Despite the capacity for large-scale

production of rhTE, the major drawback remains the requirement for extensive purification of proteins derived from bacterial systems. 4.2.4. Elastin-like peptides. In an effort to engineer the properties of elastin peptides, elastin-like peptides (ELPs) have also been widely studied. Urry was the first to report the fabrication of ELPs90. Briefly, the polypentapeptide (Val-Pro-Gly-Val-Gly)n, derived from an elastin consensus sequence, was synthesized in solution phase by mixing Boc-protected peptides groups29. Functional characterization revealed coacervation, in a similar temperature range as native α-elastin. Since then other groups have developed many ELPs ACS Paragon Plus Environment

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variants by modifying the amino acid sequence, side chains, and synthesis91–99. ELPs allow control of amino acid sequence, chain length, and chemical and biological properties. McMillan et al. modified the sequence to (Val-Pro-Gly-Val-Gly)4(Val-Pro-Gly-Lys-Gly) and used E. coli to express recombinant ELPs. This modification introduced lysine groups for potential crosslinking100.

Chilkoti studied the effect of amino acid sequence,

molecular weight, and architecture of ELP-thermal behavior through the use of recursive directional ligation, or the rapid cloning of highly repetitive polypeptides (Figure 5A)101,102. Chaikof and colleagues demonstrated that self-assembled ELPs elicited minimal inflammatory response when implanted for periods of up to one year in vivo, without the need for chemical or ionic crosslinking103, and that addition of a cell binding sequence from the matricellular protein, CCN1, to the ELP chain promoted EC adhesion, proliferation, and migration (Figure 5B)104.

Figure 5. Engineering elastin-like peptides. (A) Depiction of molecular steps in recursive directional ligation. Modified with 102 104 permission from reference . (B) Schematic of bioactive ELP. Modified with permission from reference .

5. BIOMATERIAL FABRICATION METHODS Naturally derived biomaterials have demonstrated limited evidence of local or systemic toxicity, adverse immunogenic reactions, do not require further chemical modification to promote cell adhesion, proliferation and migration; and, can be chemically and physically tuned depending on the application74,105. Considering their major role in the ECM, proteins like collagen and elastin have been used as building blocks for biomaterial fabrication.

In this section, fabrication modalities including casting, fiber spinning, and bioprinting will be

reviewed. 5.1. Casting. Casting has been a widely used manufacturing process for various biomaterials. It consists of dissolving polymers in suitable solvents to obtain viscous solutions, which are poured into molds (Figure



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6A)106.

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The solution then solidifies through solvent removal, crosslinking, neutralization, or temperature

changes. In the case of collagen, casting has been primarily used to fabricate planar and tubular scaffolds107–109. For example, type I collagen and chondroitin sulfate were dissolved in 0.05 M acetic acid and freeze-dried to produce films with tunable porosity110,111. Crosslinking has also been used to further support the fabrication of collagen films10,13,112,113. For example, Holladay et al. generated collagen scaffolds through casting, freezedrying, and subsequent crosslinking using 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide (EDC) and Nhydroxy-succinimide (NHS)114. In other instances, collagen gels were fabricated through the pH neutralization of acid-soluble collagen or recombinant collagen115,116. Rat tail type I collagen was dissolved in 10 mM HCl (pH 2.0), and neutralized using a basic phosphate-based solution (pH 8.0), as a trigger for gelation117. To allow for the fabrication of cellpopulated scaffolds, temperature has also been used to fabricate collagen matrices118. Chamberlain et al. generated cell-containing collagen gels by dissolving type I collagen and cells in a cold (4˚C) cell culture medium, casting the solution in a mold, with subsequent incubation at 37°C for 60 min to initiate gelation119. In the case of elastin, casting occurs through coacervation. All elastins, including rhTE, ELPs, and animalderived elastin and TE, maintain the capacity to aggregate above an inverse transition temperature, allowing the generation of elastin-based gels by casting elastin dissolved at 4°C and raising the temperature to above the inverse transition temperature120–122. For example, ELPs were formed into disks by dissolving in cold (4°C) PBS, pouring into molds, and incubating at 37°C103. Structural modifications have also been made to elastin biomaterials to allow for chemical crosslinking, including the addition of lysine-rich domains to facilitate aminemediated crosslinking123 or the addition of methacrylate groups to allow photocrosslinking124. 5.2. Fiber spinning. Considering that collagen and elastin biosynthesis results in fibrillar structures in native tissues, fiber spinning has been widely used for the fabrication of collagen and elastin biomaterials. Among the many fiber extrusion methods, wet spinning and electrospinning have been the most widely applied106,125. 5.2.1. Wet Spinning. Wet spinning consists of injecting a viscous polymer solution from a syringe into a non-solvent or coagulation bath, which continuously solidifies the extruded filament.

The diameter and

topography of the spun fiber is determined by the injection rate, as well as the chemical interactions between ACS Paragon Plus Environment

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the polymer solution and the coagulating bath. Caves et al. reported the use of wet spinning to generate type I collagen fibers with a diameter of 40 µm for the engineering of arterial constructs and soft tissue120,126. Briefly, rat tail type I collagen was dissolved in HCl (pH 2.0), injected (0.08 mL/min) into a basic phosphate-based buffer through a spinneret with an inner diameter of 0.4 mm, and the spun fibers were collected as a network with varying fiber spacing and orientation. 5.2.2. Electrospinning.

Unlike other spinning methods, the driving force for fiber production in

electrospinning is not mechanical extrusion but rather electrical charge. In this process, voltage is applied to a syringe needle, which charges the body of the liquid and causes an electrostatic repulsion (Figure 6B). This repulsion counteracts the surface tension of the liquid, ultimately resulting in the emission of jets of polymer solution from the surface127,128. As the jet travels, the solvent evaporates, forming a charged and continuous filament that is collected on a metal screen that disperses its charges. Over the years, both collagen and elastin have been electrospun. Chaikof and colleagues were among the first to report the formation of collagen and elastin nanofibers through electrospinning129,130. In the case of collagen, rat tail type I collagen and poly(ethylene oxide) [PEO] were mixed in 10 mM HCl (pH 2.0), extruded at ambient temperature and pressure at a defined flow rate through a positively charged metal blunt needle (22 G), and collagen-PEO fibers were collected on grounded aluminum plates129. Electron microscopy revealed uniform fibers with diameters between 100-150 nm, and tensile testing demonstrated that strength and elasticity could be tuned by changing the weight ratios of each constituent. Many groups have electrospun collagen fibers in order to fabricate fibrillar networks through physical and chemical crosslinking, and used these structures to study cell behavior and engineer tissues131–134. Elastin fibers and networks have also been fabricated through electrospinning22,85,135.

Huang et al.

published the first report of electrospun elastin fibers130. Briefly, ELPs were expressed by E. coli, dissolved in distilled, deionized water at various concentrations, extruded at ambient temperature and pressure at a defined flow rate through a positively charged metal blunt needle, and collected on grounded aluminum plates (22 G)130. ELP-fiber imaging revealed that processing parameters influenced both fiber diameter (200 – 3000 nm) and morphology. 5.3. Bioprinting. Three-dimensional (3D) printing is a term referring to additive manufacturing, as first described by Charles Hull in 1986136.

He reported the fabrication of complex 3D structures through



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stereolithography, a technique that relies on the photopolymerization of materials that are sequentially deposited as thin layers. Since then, many 3D printing modalities have been developed, including bioprinting. Bioprinting consists of computer-aided transfer processes for patterning and assembling structures through the combination of biomaterials, growth factors, and cells137. Common bioprinting techniques used to fabricate biomaterials have included inkjet, microextrusion, and laser-assisted bioprinting methods (Figure 6C)138. 5.3.1. Inkjet Bioprinting. Inkjet printing, the most common technique for bioprinting, relies on the delivery of controlled solution volumes to predefined locations. These printers resemble commercial 2D inkjet printers, with the main difference being the use of thermal or acoustic forces to eject biomaterials onto substrates and fabricate 3D structures layer-by-layer. The advantages of inkjet printers include high speed, low cost, and wide availability; yet the risk of overheating biomaterials, as well as frequent clogging of the nozzle pose considerable disadvantages. Another limitation of this technique is the requirement for rapid crosslinking kinetics (within seconds to minutes), thus, the most popular biomaterials for inkjet printing have included calcium crosslinked alginate, photocrosslinked methacrylated synthetic polymers, and photocrosslinkable hydrogels139–143. Nonetheless, although collagen gelation is slower (within minutes to hours), inkjet-printing has been used to fabricate collagen scaffolds through pH-triggered144,145 and temperature-triggered gelation146. 5.3.2. Microextrusion bioprinting.

Microextrusion printing, the most affordable technique, consists of

material dispensing in a controlled fashion using pneumatic or mechanical forces to extrude viscous solutions, which quickly solidify and support the extrusion of subsequent layers138.

The main advantage of

microextrusion bioprinting is a high cell density loading capacity, although cell viability appears lower than that of inkjet printing147.

The most commonly used polymers in this method are those that can be thermally

crosslinked or that possess shear-thinning properties138,148. Johnson et al. used a microextrusion printer to fabricate a methacrylated-gelatin hydrogel for nerve regeneration and Duan et al. fabricated alginate-gelatin scaffolds as aortic valves replacements149,150. Similarly, Kolesky et al. printed 3D vascularized structures using gelatin and vascular cells, and demonstrated that tissues exceeding 1 cm in thickness can be perfused on-chip for up to 6 weeks151. 5.3.3. Laser-assisted Bioprinting.

Laser-assisted bioprinting (LAB) is a nozzle-free system that uses

focused laser pulses to generate high-pressure bubbles that propel materials from one substrate to another. The main advantage of LAB is its high resolution, which is influenced by the energy of the laser, surface ACS Paragon Plus Environment

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tension, wettability of the donor substrate, and the air gap distance between the two substrates138. Other advantages include the absence of nozzle clogging and the capacity to achieve large cell-seeding densities (108 cells/mL). The main limitation of LAB is a requirement for rapid gelation kinetics, which poses a challenge for printing collagen and elastin biomaterials. Nonetheless, collagen scaffolds have been fabricated using LAB through pH-triggered gelation. Michael et al. demonstrated that type I collagen could be arranged into 3D skin constructs through the use of LAB152. Guillotin et al. have used LAB to fabricate cell-containing alginatecollagen constructs and demonstrated microscale level control of cell deposition153. Biomaterial printing offers the promise of fabricating tissues and organs through direct printing of biomaterials into defects. Currently, most efforts use non-naturally-derived molecules for mechanical support or as a sacrificial material that facilitates cell growth and remodeling. Thus, these approaches remain largely limited by a requirement for the deposited cells to recapitulate tissue through direct synthesis of structural proteins, such as collagen and elastin; a process which often requires months to achieve while the construct is maintained in a bioreactor or following implantation.

Figure 6. Biomaterial fabrication modalities. (A) Casting. (1) Collagen is casted on a rectangular mold. Image modified with 121 120 permission from reference . (2) SEM image of a casted collagen film. Image modified with permission from reference . (B) 106 Electrospinning. (3) Schematic of electrospinning setup. Imaged modified with permission from reference . (4) SEM image of an electrospun fiber network. (C) Bioprinting. Schematic and pictures of (5,8) inkjet, (6,9) microextrusion, and (7,10) laser-assisted 138 bioprinting. Images modified with permission from reference .

6. CLINICAL APPLICATIONS 6.1. Cardiovascular Tissues. The engineering of cardiovascular tissues, including blood vessels, heart valves, and myocardial patches has benefitted significantly from developments in collagen and elastin biomaterials. Cardiovascular disease affects over 71 million people in the United States alone; with over 7 million inpatient visits and 500,000 bypass surgeries performed annually154. Due to the growing prevalence of ACS Paragon Plus Environment


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cardiovascular disease, we foresee a continued emphasis to surmount existing challenges of cardiovascular tissue engineering. 6.1.1. Blood Vessels.

Synthetic vascular grafts commonly suffer from acute thrombosis; bacterial

colonization and infection; compliance mismatching that can result in intimal hyperplasia; and, ultimately, an inability to grow and adapt which hinders their utility in pediatric patients155. In the clinical setting, autologous vascular conduits, such as saphenous veins, remain the gold standard for bypass grafting156,157. Nonetheless, autografts have limited availability, as many of the patients do not have suitable vessels158,159.

These

limitations have motivated the development of tissue-engineered vascular grafts (TEVG). Collagen, particularly type I, is the most prevalent extracellular matrix protein of blood vessels, being widely distributed among all three layers, or tunicae, of the vascular wall. Collagen is required both as a load-bearing element and as a mediator of local biological responses. In the tunica intima it serves as a signaling substrate for endothelial cell growth, while in the tunica media it provides mechanical support and tensile stiffness for rupture resistance160.

Similarly, elastin is a critical determinant of both the biological properties and

biomechanical responses of blood vessels where it constitutes 30-50% of the dry weight of an arterial wall160,161.

Thus, in an attempt to design arterial substitutes by mimicking the microstructure of arteries,

vascular tissue engineers have increasingly developed grafts incorporating collagen and elastin biomaterials. In 1986, Weinberg and Bell were the first to report a small-diameter TEVG, which consisted of a tubular collagen gel scaffold, bovine aortic cells and a Dacron mesh for mechanical support109. Despite the limited mechanical properties of the graft, the authors identified the lack of elastin as a significant limitation of their approach, and confirmed by others160.

Nonetheless, the majority of biomaterial-based TEVGs that have

followed have largely not incorporated elastin into their design162–167. The first reports of elastin-containing TEVGs were published in the 2000s. Briefly, collagen (insoluble and acid-soluble) and elastin isolated from various sources were mixed and fabricated into TEVG through the use of freeze-drying, casting or electrospinning approaches168–170. Koens et al. combined animal-derived type I collagen and elastin, and fabricated triple layered constructs with an inner layer of elastin fibers and outer layers of collagen fibrils (Figure 7A)171. Since then, many groups have incorporated elastin within the design of TEVG (Table 1). For example, Weiss generated parallel elastic fibers from recombinant human tropoelastin as a model of the tunica media to ACS Paragon Plus Environment

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assess alignment of SMCs172. Elastin-collagen grafts were also obtained through decellularization of porcine carotid arteries, with significant cellular infiltration after subdermal implantation173,174.

Others have mixed

elastins with synthetic polymers, and electrospun fibers of controlled diameter, mechanical properties and degradation profiles175–177. More recently, ELPs have been used in vascular tissue engineering due to their capacity to modulate mechanical properties and introduce cell-binding domains (Table 1)178,179. For example, Caves et al. and Kumar et al. have fabricated ELP-collagen composite grafts with mechanical properties closely matching native small-diameter arteries126, and implanted as aortic interposition grafts in rats (Figure 7B)121.

They

demonstrated that arterial-like suture retention, burst pressure and compliance could be achieved by controlling elastin content as well as collagen fiber spacing, fraction, and orientation.

Figure 7. Tissue engineering vascular grafts that combine collagen and elastin. (A) Elastin van Geison staining of triple layer 171 vascular graft: collagen stained pink and elastin blue/black. Modified with permission from reference . (B) Van Geison stained cross121 section of graft wall delineating layers: collagen stained red, elastin yellow. Modified with permission from reference .

Elastin biomaterials, including elastins, tropoelastins, and ELPs, have also been used to coat the luminal surface of prosthetic grafts and stents as a means to limit thrombotic responses at the blood-material interface180–184. Small-diameter expanded polytetrafluoroethylene (ePTFE) grafts have been impregnated with recombinant ELP with minimal acute platelet deposition in a femoral arteriovenous shunt model in baboons180.

Table 1. Collagen and Elastin Biomaterials in Blood Vessel Engineering Biomaterials

Sources

Fabrication Modalities

Crosslinking Agents

References

Collagen

Animal-derived collagen

Tubular casting - Temperature triggered gelation

Elastin

Porcine aorta

Tissues were treated with cyanogen bromide to remove cells and collagen

Recombinant human tropoelastin

Electrospinning

Diisohexanecyanate

172


Electrospinning

Glutaraldehyde

175,176

Elastin-PCL


109 173,174


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Collagen-Elastin

Rat-tail type I collagen and porcine carotid elastin Bovine tendon type I collagen and equine ligament elastin Calfskin type I collagen and equine ligament elastin


168

Tubular casting - Lyophilization

EDC-NHS

169,171

Electrospinning

EDC-NHS

170,177

Glutaraldehyde

126

Rat-tail type I collagen and elastin-like peptides

Wet Spinning of collagen fibers embedded in tubular casted ELP matrix

Rat-tail type I collagen and elastin-like peptides

Film casting - pH triggered gelation

6.1.2. Cardiac Tissue.

Page 16 of 34

121

Cardiac tissue engineering has also benefitted from elastin and collagen

biomaterials. Despite the current incapacity to regenerate myocardium, engineers have developed various tissue models and implantable devices over the past decade (Table 2). For example, Annabi et al. used methacrylated recombinant human tropoelastin to fabricate micropatterned, thin films of photocrosslinked hydrogels, which were seeded with cardiomyocytes (CM) as a model of myocardium (Figure 8)124,185.

1

Figure 8. Methacrylated recombinant human tropoelastin. (A) Representative H NMR spectrum of tropoelastin and MeTro solutions at 4°C. Representative cross-sectional SEM images of (B) 10% and (C) 15% (w/v) 31%-methacrylated TE hydrogel. 185 Modified with permission from reference .

Type I collagen has been used to fabricate porous scaffolds to study the behavior of CM, as well as attempt to regenerate cardiac tissue114,118,186–190. For example, Radisic et al. cultured CM in collagen sponges and observed enhanced cell alignment, coupling, synchronous construct contractions, and ultrastructural organization after 8 days of electrical stimulation191. Others have fabricated thick, force-generating cardiac layers by seeding CM in collagen rings, stacked to form multiloops192. These tissues were implanted in mice after myocardial infarction. Physiological beating of rings was observed four weeks after implantation without evidence of arrhythmia, dilation, and with improved left ventricular function. Table 2. Collagen and Elastin Biomaterials in Cardiac Engineering


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Biomaterials

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Sources


Crosslinking Agents

References

Animal-derived collagen


118

Rat tail type I collagen

Ring casting - Temperature triggered gelation

192

Type I collagen

Film casting - Temperature triggered gelation

187

Type I collagen

Film casting - Lyophilization


Cylindrical casting - pH triggered gelation

Elastin


Film casting - Coacervation

Collagen-Elastin

Rat tail type I collagen and bovine ligament elastin


Collagen-GAGs

Bovine hide type I collagen


Collagen

6.1.3. Heart Valves.

EDC-NHS

114,191 188

Photocrosslinking

124,185 190

Dehydration treatment

186

Most efforts in heart valve engineering have focused on the use of fibrin-based

scaffolds, decellularized tissues, biodegradable synthetic polymers, and cell sheets193–198.

Nonetheless,

despite the abundance of collagen and elastin within valve leaflets, particularly the ventricularis layer, efforts to produce composites from collagen and elastin have been limited199. Collagen-glycosaminoglycan gels seeded with porcine mitral valve interstitial cells have been investigated200. Shi et al. have also explored the fabrication of independent aortic valve cusps by casting type I collagen, with subsequent assembly into complete aortic valves (Figure 9)201.

Figure 9. (A-D) Examples of various mold geometries used to cast type I collagen constructs for heart valve engineering. (E) 201 Cellularized collagen construct cultured for 4 weeks. Images reprinted from reference .

6.2. Musculoskeletal Tissues. Musculoskeletal disease affect almost 50% of the United States population and results in 34 million surgical procedures every year202.

Although the conditions range from acute to

chronic, and span over a range of tissues, including tendon, ligament, meniscus, cartilage and bone, reconstructive surgery has relied upon allografts, autografts, non-tissue prosthetics, as well as tissue engineering approaches203. The latter are reviewed in the following section. ACS Paragon Plus Environment


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6.2.1. Cartilage. Cartilage is a flexible connective tissue with properties that vary depending on location and function. Hyaline cartilage is a highly resilient tissue that covers the ends of bones and serves as a lubricating surface to allow for frictionless movements204,205. Elastic cartilage, found primarily in the ear and epiglottis, is more elastic and can withstand repeated bending. Although the composition of cartilage can vary, all types are mainly composed of chondrocytes and ECM, including type II collagen, elastin, and other proteoglycans204. When subjected to injury, cartilage often heals through scar formation, resulting in fibrocartilage. Fibrocartilage differs significantly from healthy cartilage in its biochemical and biomechanical properties and can lead to osteoarthritis206. Considering the importance of type II collagen in cartilage, collagen-based scaffolds have been widely used in research and in the clinic (Table 3). Extensive pre-clinical studies have demonstrated the feasibility of collagen (type I, II and III) scaffolds in regenerating cartilage in various animal models due to low immunogenicity, ease of manipulation, capacity to achieve high seeding efficiency, and mechanical support207,208.

For example, crosslinked porous collagenous matrices, prepared by lyophilization of acid-

soluble collagen, were implanted on full-thickness femoral trochlea defects of rabbits113.

Histological

evaluation 12 weeks post-implantation reveal complete restoration of the trochlea. Clinically, porcine-derived mixed collagen (type I and II) membranes are commonly used during cartilage reconstructive surgery, including matrix-induced autologous chondrocyte implantation209–212. Elastin-based biomaterials have also been used for cartilage engineering (Table 3)74,213.

Porous poly-

caprolactone scaffolds impregnated with bovine elastin demonstrated improved mechanical and biological responses214. Chondrocytes cultured on coacervated or enzymatically crosslinked ELP hydrogels were shown to promote chondrogensis in vitro215,216. Chilkoti and Setton developed a mechanically robust, chondrocytecontaining scaffold that was capable of integrating into an osteochondral defect in a goat model with significant production of hyaline-like ECM123. Table 3. Collagen and Elastin Biomaterials in Cartilage Engineering Biomaterials

Sources


Crosslinking Agents

References

Collagen

Porcine collagen I and III


209,210,212

Elastin

Elastin-like peptides


215,216



THPP

123

Bovine tendon type I and bovine tracheal cartilage type II collagen


EDC-NHS

113

Collagen-CS


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Elastin-PCL

ACS Biomaterials Science & Engineering Bovine ligament elastin

PCL scaffold impregnated with elastin

Glutaraldehyde

214

6.2.2. Tendons and Ligaments. Collagen type I fibrils account for 60% of the dry mass of tendons and ligaments217. These fibers are responsible for transferring forces between various musculoskeletal tissues. For this reason, collagen scaffolds have been widely studied to promote tendon and ligament repair218–221. For example, Murray et al. fabricated collagen-platelet rich plasma (collagen-PCP) hydrogels, which 4 weeks postimplantation in pigs demonstrated similar biomechanics as native ACLs222. Other groups have combined collagen with synthetic polymers in an effort to increase the mechanical strength of the constructs (Figure 10)125,217,223–225. Panas-Perez et al. mixed bovine type I collagen and silk fibers, and demonstrated that the constructs maintain sufficient strength 8 weeks after subcutaneous and intraarticular implantation in rabbits226.

Figure 10. Picture of braided hybrid scaffold (75% p(DTD DD) and 25% type I bovine collagen). Reprinted with permission from 224 reference .

Elastin constitutes 4% of tendons and 50% of elastic ligaments, and can be found as parallel-oriented ropelike fibers throughout the length of these tissues74. Nonetheless, elastins have largely not been explored for tendon and ligament engineering. Future work should explore the possibility of enhancing the mechanical and biological properties of these constructs by the incorporation of elastin biomaterials in order to better mimic musculoskeletal tissues microstructure227,228. 6.3. Skin. Skin serves to protect the body from infection, regulate body temperature, and prevent fluid losses. Although collagen type I is the most prevalent protein in skin, elastin constitutes 2 to 5% of its dry weight and provides elasticity to withstand frequent deformations74,229. The importance of both collagen and elastin has motivated the use of both biomaterials in dermal tissue engineering.



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Approximately 11 million patients worldwide suffer severe burns every year with estimated annual deaths of 265,000230. Split-thickness skin grafts remain the most commonly used approach for treating wounds, in which autologous skin consisting of epidermis and the superficial dermis are transplanted from a donor site to a recipient wound bed231,232. This technique remains associated with donor site morbidity, as well as scarring in the recipient site. For this reason, the potential to engineer living skin has been investigated (Table 4)132,233. Over the years, many biomaterials have been explored, including collagen, fibrin, and synthetic polymers234– 237

. Yannas et al. demonstrated that porous scaffolds fabricated by lyophilizing casted mixtures of type I

collagen and chondroitin sulfate (CS) can delay wound contraction in guinea pigs for 10 days110,238. This scaffold is now the leading synthetic skin substitute. Recombinant collagen has also been used for skin engineering. Nuutila et al. used recombinant human collagen III (rhCol-III) for the delivery of cultured autologous skin cells to full-thickness wounds in pigs, which enhanced early granulation tissue formation116. Similarly, Willard et al. fabricated electrospun and castedlyophilized scaffolds from recombinant human type I collagen (rhCol-I), and demonstrated an improved humancell attachment and proliferation compared to animal-derived collagen scaffolds69. More recently, elastin biomaterials have been explored as components of dermal tissue engineering (Table 4). Claiming that collagen-based scaffolds suffer from severe contraction, the Weiss group has explored the development of elastic, protein-based, fibrous scaffolds239,240.

Porous scaffolds were fabricated by

electrospinning recombinant human tropoelastin into 3D fibrous networks with tunable porosity. In vitro studies demonstrated fibroblast adhesion, infiltration, and remodeling, while subdermal implantation in mice did not promote wound contraction241. Tropoelastin has also been used to increase rates of angiogenesis and neodermis formation. For example, recombinant human tropoelastin has been added to the lyophilized collagen-CS scaffold developed by Yannas242. Mechanical and histological characterization revealed increased elasticity compared to the nonrhTE scaffold (Figure 11), and accelerated angiogenesis with limited wound contraction, two weeks after implantation in mice and pigs.

Other collagen-elastin scaffolds have been developed by electrospinning

collagen and elastin243. Rnjak-Kovacina et al. reported that mixtures consisting of 80% type I collagen and 20% recombinant tropoelastin enhanced fibroblast proliferation and migration rates in vitro, without evidence of adverse biological responses 6 weeks after subcutaneous implantation in a mouse model. ACS Paragon Plus Environment

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Figure 11. Mechanical characterization of rhTE-collagen-CS (TDRT) and collagen-CS scaffold (IDRT), including (A) stress – 242 strain, (B) Young’s modulus, (C) energy loss, and (D) ultimate elastin strain. Modified with permission from reference . Table 4. Collagen and Elastin Biomaterials in Skin Engineering Biomaterials Collagen

Sources


Crosslinking Agents

References

EDC-NHS

132

Bovine type I collagen

Electrospinning

Type I collagen

Inkjet bioprinting


Laser-assisted bioprinting

152

Recombinant type III collagen


116

Recombinant type I collagen


69

Recombinant type I collagen

Electrospinning

EDC

69

Elastin


Electrospinning

Glutaraldehyde

239,241

Collagen-CS

Bovine hide type I collagen


Glutaraldehyde

110,238

Collagen-Elastin

Bovine skin type I, III, and V collagen, and bovine ligament elastin

Film casting

Recombinant human tropoelastin and type I collagen


Glutaraldehyde

242

Recombinant human tropoelastin and ovine collagen

Electrospinning

Glutaraldehyde

243

145,146

233

6.4. Liver. Liver disease results in 27,000 deaths annually in the United States and as of 2013, over 17,000 patients were awaiting liver transplants, with only 6,000 organs transplanted each year244. The shortage of livers has motivated tissue-engineering alternatives. Type I collagen initially proved to be a suitable 2D substrate for culturing hepatocytes245, and more recently, collagen has also been incorporated to 3D polymeric-structures that include synthetic polymers and polysaccharides to enhance hepatocyte culture (Table 5)246–250. For example, bovine type I collagen was mixed with a polysaccharide to form a non-cell adherent scaffold that promoted formation of hepatocyte spheroids under microgravity251.



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Page 22 of 34

Efforts to generate larger livers constructs using collagen biomaterials have also been pursued (Table 5). Takebe et al. developed vascularized hepatic-like tissues by combining fetal liver cells with mesenchymal stem cells in a collagen/fibronectin matrix, assembled through the temperature-triggered gelation of rat-tail type I collagen252. In another instance, collagen-alginate spheres were used to package large numbers of cells and to provide immune protection253. Eight weeks after implantation in mice, spheres were harvested, revealing a microstructure similar to hepatic tissue with limited inflammation. Despite the presence of elastin in liver tissues, elastin biomaterials have had limited utility in hepatic engineering.

Most efforts have focused on enhancing hepatocyte 2D cultures, spheroid formation and

functional characterization (Table 5). Janorkar et al. demonstrated that ELPs conjugated with polyethylenimine (PEI) enabled control over the in vitro morphology and liver-specific function of primary rat hepatocytes254,255. Positively charged ELP-PEI substrates promoted hepatocyte aggregation and spheroid formation. These results suggest benefits from incorporating both collagen and elastin biomaterials in tissue engineering designs. However, to better mimic the microstructure of liver, future efforts should explore the combination of both biomaterials.

Figure 12. (A) Morphological observation over 30 days of collagen-alginate spheres seeded with hepatocytes. Modified with 253 permission from reference . (B) Hepatic spheroids only form when hepatocytes are cultured on ELP-PEI substrates. Reprinted with 254 permission from reference .

Table 5. Collagen and Elastin Biomaterials in Liver Engineering Biomaterials Collagen

Sources Rat tail type I collagen


Crosslinking Agents



References 245,246,250,252

Page 23 of 34

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Elastin

ACS Biomaterials Science & Engineering Type I collagen

Film casting - Drying

EDC-NHS

247

Type I collagen


248

Type I collagen

PLLA fibers coated with collagen

249

Bovine dermal type I collagen


Glutaraldehyde

251



EDC-NHS

254,255

7. OUTLOOK Tissue engineers can now choose from a wide array of potential biomaterials and fabrication modalities in the design of tissues and organs.

These biomaterials can range from synthetic polymers with tunable

mechanical properties and degradation profiles to minerals found in the shell of marine animals. Collagen and elastin biomaterials offer the promise to revolutionize the way we engineer living tissues. They constitute the two most prevalent proteins in the body, and serve crucial biological and mechanical roles. In many regards, the body is a reinforced composite of collagen and elastin motivating future efforts in tissue engineering, which seek to incorporate both biomaterials as building blocks in organ and tissue fabrication. Many approaches currently use collagen or elastin biomaterials that are manipulated using various methods to engineer tissues. We have highlighted a subset of these approaches in this review. However, efforts to truly recapitulate the collagen-elastin composite nature of tissues are still limited, often relying on cell-mediated synthesis of the missing constituent. This requirement substantially slows down fabrication processes and can result in inadequate structures that lead to maladaptive remodeling and tissue failure. We believe that it remains advantageous to better mimic the ECM by selecting these two proteins as primary building blocks, which together with fabrication modalities, such as bioprinting, may allow for enhanced controlled of matrix structure and composition.

AUTHOR INFORMATION Corresponding Author: * E-mail: [email protected] Author Contributions: All authors contributed in the writing of the manuscript. Notes: ACS Paragon Plus Environment


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Page 24 of 34

The authors declare no competing financial interest.

ACKNOWLEDGEMENTS This work was supported by grants from the NIH (RO1HL083867, RO1HL60464, and RO1HL71336). DMN acknowledges financial support from the National Defense Science and Engineering Graduate (NDSEG) Fellowship.

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For Table of Contents Use Only: Collagen

Fabrication

Living Tissues

Elastin



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For Table of Contents Use Only: Collagen

Fabrication

Living Tissues

Elastin


Page 34 of 34

Collagen and Elastin Biomaterials for the Fabrication of Engineered

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