Sustainable Biomass Materials for Biomedical Applications - ACS

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Sustainable Biomass Materials for Biomedical Applications Yi-Chen Li ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/acsbiomaterials.8b01634 • Publication Date (Web): 22 Mar 2019 Downloaded from http://pubs.acs.org on March 23, 2019

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ACS Biomaterials Science & Engineering

Sustainable biomass materials for biomedical applications 47x31mm (300 x 300 DPI)

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Sustainable Biomass Materials for Biomedical Applications Yi-Chen Ethan Li* Department of Chemical Engineering, Feng Chia University, 40724, Taichung, Taiwan. e-mail: [email protected] Abstract Renewable resources are abundant worldwide in the form of raw materials, which come from terrestrial/marine animals, agricultural plants, microorganisms, and their residues. Sustainable biomass materials derived from these raw materials have provided an opening for the development of new alternatives to replace traditional petromaterials for different purposes, including green energy, paint, food packaging, and biomedical applications. In this review, we highlight the potential use of various sustainable biomass materials in three dimensional/four dimensional (3D/4D) bioprinting, drug delivery/controlled release, tissue engineering, and biosensing applications. We then discuss the features of sustainable biomass materials in association with the basic requirements of these applications, such as printability, sensitivity, mechanical properties, and modifiability. We finally conclude with future perspectives. Keywords: Sustainable biomass materials, 3D/4D bioprinting, drug delivery, controlled release, tissue engineering, biosensors.

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1. Introduction to sustainable biomass materials Polymers derived from traditional petro-materials contribute considerably to progressive improvements in the quality of modern life. However, the use of petropolymers has some underlying disadvantages related to environmental pollution and end-of-life options. For example, Derraik and coworkers showed polyethylene- and polypropylene-based plastics with minimal biodegradation properties and high resistance of aging, causing marine litter comprising 60% to 80% of plastic debris1. Although synthetic plastic from petroleum is broken into smaller pieces when exposed to UV radiation in sunlight, the small pieces are still plastic and difficult to be biodegraded, leading to an increasingly abundant plastic debris in our environment2. In the last few years, renewable resources have provided an opening for the development of novel sustainable biomass materials for use in our daily lives. Sustainable biomass materials derived from raw materials are of prime interest to develop alternatives to traditional petro-materials for different purposes, such as green energy, paint, food packaging, and biomedical applications3-4. For example, the application of sustainable materials in composites decreases fuel consumption in public/personal transport5, and their application in materials enables the fabrication of biological degradable food packaging6. Raw materials from terrestrial/marine animals, agricultural plants, microorganisms, and their residues are the most biologically renewable resources that can be isolated and extracted from sustainable biomass materials, especially agricultural plants. Every year, the raw materials produced from the wood processing industry and agricultural/forestry fields are estimated to total more than 500 million metric tons7. Additionally, the annual production of raw materials from ocean plants and crustacean animal residues are other common sources to produce sustainable biomass materials8-9. All the information indicates that these raw materials and their residues are abundant renewable sources in the world for the production of sustainable biomass materials. Moreover, utilizing biomass-based materials not only benefits environmentally related aspects, such as greenhouse gas mitigation but could also generate high-value biomass products (e.g., biomass energy)10 from renewable raw materials and their residues. In the last decade, sustainable biomass materials have been widely used for energy and food packaging applications. For example, corn stover has been utilized as a source of biomass energy worldwide11, and cellulose and its derivatives endow current polylactic acid barriers with robust mechanical properties for application in food packaging12. Recently, in the biomedical field, the applications of biomass materials have been extended from drug capsules to smart controlled release, tissue engineering, and other areas13-14 because of the biocompatibility, biodegradability and nontoxicity 2 ACS Paragon Plus Environment


of these materials15. Several types of sustainable biomass materials—cellulose, lignin, alginate, chitosan, silk, and gelatin—are widely applied in the fabrication of substrates/scaffolds, drug carriers, and biosensors, among others. For example, alginate-based sponges are used as gastroretentive carriers to control the release of loaded tetrahydrocurcumin and β-lapachone for the treatment of gastric dieases16. Additionally, cellulose-based materials with less thrombogenic effects than commercial poly(vinyl-alcohol)-based electrodes enable them to be used as a glucose biosensor for human blood samples.17-18 In addition to their biological properties, these materials are abundant in agricultural and animal wastes, making them attractive for use in biomedical applications. For example, in nature, the content of cellulose in the cell walls of plants is close to 40%,19 making cellulose the ubiquitous component to contribute its mechanical properties to plant cells20; gelatin is a common sustainable protein-based biomaterial that exists in the skin and connective tissues of animals21. Although sustainability is not the most important requirement for the selection of biomaterials for biomedical applications, it is desirable to reduce the use of plastic biomaterials, enabled by the abundant sources of biomass materials. Moreover, the abovementioned examples prove biomass materials can exhibit fundamental and important biological properties such as biocompatibility and blood compatibility,13-18 showing that biomass materials have potential for use in biomedical applications. Here, from another point of view, we examined current advanced biomedical applications, including the bioinks of three dimensional/four dimensional (3D/4D) bioprinting, drug delivery/controlled release, tissue engineering, and biosensing, to highlight how sustainable biomass-based materials are utilized in biomedical studies. With this review, we expect to provide an overview that will enable scientists to understand the needs of these advanced biomedical applications, further apply sustainable biomass materials, and create biomass materials with new potential functions for applications in the biomedical field.


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2. Biomedical applications 2.1. Biomass material-based inks for 3D/4D Bioprinting In the last five years, engineered artificial tissues have attracted increasing attention for use as alternatives to repair damaged tissues or as in vitro models to evaluate the responses of the human body to pharmaceutical compounds. Compared with the synthesized biocompatible materials, some natural materials from biomass with saccharide or protein structures are considered with higher biocompatible and biodegradable properties that can be degraded in vivo22; their degraded products have less impact, and some of them, such as glycine and CO2, could be eliminated or reused in human body23. Therefore, these types of biomass materials are suitable candidates as biomaterials for making artificial tissues. Recently, 3D printing is one of the technologies that has been thoroughly developed to rapidly fabricate three-dimensional complex structures. To build engineered tissues with structures more closely resembling those of real tissues, researchers have begun to employ 3D printing technologies, named 3D bioprinting, as a new biofabrication technique to make biomimetic tissue constructs. Obviously, the fast and precisely controllable process endows 3D bioprinting with versatile functions, and, as a result, numerous bioengineers have devoted their attention to extending the applications of 3D bioprinting technologies in the biomedical field, such as in the preoperative simulation of surgery24. Inkjet and microextrusion printing are two common techniques used in the 3D bioprinting field. In these two printing techniques, the bioink plays a fundamental role in deciding the quality of the printed constructs. One of the basic properties required to make bioinks suitable for printing technologies is the dispensability, meaning that the rheological properties of the material must fit the printable requirements of bioinks (i.e., shear thinning behavior)25. Additionally, the physical properties are also important factors in bioprinting technologies: (1) the viscoelasticity protects cells from shear stress; (2) the biocompatibility determines the cell viability after the printing process; and (3) the gelation kinetics maintain the fidelity of the bioprinted structures26. In general, if sustainable biomass materials possess linear polysaccharide chains, these linear chains easily extend and move around in solution to form entangled networks through hydrogen bonding, ionic, and Van der Waal interactions, thereby increasing the viscosity or gelation ability of the biomass material solution at modest concentrations. In other words, linear polysaccharide chains endow most sustainable biomass material solutions with pseudoplastic behavior, enabling them to be utilized as printable bioinks for 3D bioprinting. Cellulose and its derivatives are linear polysaccharide biomass materials derived from agricultural raw materials and consist of β-(1,4)-linked D-glucose units with amorphous and crystalline areas27. These crystalline areas impart high stiffness in 4 ACS Paragon Plus Environment


cellulose-based biomaterials; the mechanical properties of these biomaterials allow them to be applied as pure bioinks in the fabrication of printed constructs or as additives to thicken low-viscosity bioinks and prevent the collapse of the structure after printing28-30. The printability of cellulose-based materials has been demonstrated by Karl and coworkers31. The researchers used cellulose nanofibril (CNF) hydrogels with shear-thinning behavior as an ink with a microvalue printer to directly print a CNF grid cube (Figure 1a). In addition to CNF, another type of cellulose derivative, methylcellulose, has also been used as a thickening agent in blends with alginate to obtain an ink with the desired mechanical properties30. In accordance with the unique gelling properties of methylcellulose, the addition of methylcellulose successfully eliminated the collapse of pure alginate-based printed fibers and constructs (Figure 1b). Alginate is a polysaccharide obtained from seaweed whose good biocompatibility and thixotropic properties makes it an attractive bioink candidate for 3D bioprinting32. Gao and coworkers recently developed a novel hybrid cell-laden alginate bioink by mixing alginate with vascular tissue-derived extracellular matrix (ECM) and endothelial progenitor cells33. This hybrid bioink enabled the direct fabrication of hollow tubular vessels by using a 3D coaxial bioprinting technique. Notably, the polysaccharide chains of alginate consist of an α-(1,4)-linked L-guluronic acid structure. This α-(1,4)-linked chain configuration provides an “egg-box” structure in the alginate chains that can form physical crosslinks with divalent mental ions34, which is useful for building structures during the bioprinting processes35-37. Based on this feature, Hinton et al. further combined an alginate-based bioink with an embedded printing technique to fabricate free-standing tissue constructs, such as a heart, and successfully reproduced the complex biological structures34 (Figure 1c). Gelatin is a protein-based biomaterial obtained through the partial hydrolysis of collagen from animal waste materials. Because its components are similar to those of collagen, gelatin has a high biocompatibility and biodegradability and is widely used in biomedical applications. The shear-thinning behavior of gelatin has been reported in previous studies38-39. One of the pioneers in the 3D printing field, Lewis and her coworkers, used gelatin-based materials as both an ECM and a bioink to fabricate 3Dengineered microfluidic constructs replete with multiple types of cells, hollow vascular channels, and ECM40 (Figure 1d). In their studies, the printed 3D-vascularized tissues showed good perfusability. Importantly, one feature of gelatin is its spontaneous gelation ability, which allows gelatin to form a gel in the absence of other reagents. Liu et al. utilized this feature to develop a pure gelatin-based gel through a simple cooling process that enabled the 3D printing of cell-laden constructs with high structural fidelity and a cell-friendly environment41.


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Tissues can dynamically respond to changes in the biological environments in the human body. To fabricate printed constructs that more strongly resemble real tissues, a novel bioprinting technique, 4D bioprinting, has been developed. The concept of 4D bioprinting is adding shape transformation as the fourth dimension onto 3D-printed constructs; this added fourth dimension endows the printed constructs with a dynamic deformation ability when giving appropriate stimulations42. By this concept, 4D bioprinting enables the printed constructs to mimic the dynamical changes of tissues in the biological environments43. Recently, Gladman and their coworkers used a mixture of cellulose nanofibrils and acrylamide as a bioink to mimic plant cell walls and printed a flower shape44. Next, by controlling the orientation of the cellulose nanofibrils in the bioinks that defined the swelling and elastic anisotropies of the printed constructs, the printed constructs were given a dynamic transformation ability after swelling. Additionally, the stimuli responsiveness of a material is a key factor that endows printed constructs with a transformation capability. For example, the thermoresponsive property of gelatin has been used to develop a smart shape-memory material45. This result indicates that the stimuli-sensitive properties of polysaccharide, such as thermo, pH-, and enzyme-sensitive properties46, give biomass materials the potential for application as bioinks in the 4D bioprinting technique. 2.2. Drug delivery/Controlled release The materials applied as drug carriers or drug capsules should enable drugs to be delivered to the right place and at the right time. Therefore, developing ideal materials for drug delivery and controlled release has attracted the interest of numerous pharmaceutical scientists. Polysaccharides are widely used as drug carriers because of their biocompatibility and biodegradability. Moreover, the presence of numerous types of active residues, such as amino groups, carboxylic acids, and hydroxyl groups, give polysaccharides the ability to perform various functions, such as the direct/indirect binding of biomolecules through covalent or noncovalent bonds and release of biomolecules for different purposes. For example, the amino group of chitosan provides a site to conjugate a pH-triggered drug via the amidation of dicyclohexyl carbodiimide (DCC)/N‐hydroxysulfosuccinimide (NHS)47. By this design, the conformation of drugconjugated chitosan can change from a coiled into an uncoiled morphology when the pH value changes from 7.4 to 6.8. Next, the pH-triggered drug on the chitosan backbone can generate additional singlet oxygens to provide a phototoxicity effect for cancer cells. In addition to functioning through covalent bonds to bind biomolecules, positively charged polysaccharides and negatively charged RNA or DNA can also assemble into core-shell gene nanovectors via noncovalent bonds to prevent the degradation of RNA/DNA48. 6 ACS Paragon Plus Environment


Lignin is the second-most abundant component (content of approximately 15-35%) in biomass materials. Lignin and its derivatives contain phenylpropane units and phenolic and aliphatic hydroxyl groups, which allow them to respond to stimuli or be further modified49. Recently, lignins from different species or extraction methods have been used as carriers in drug delivery/controlled release studies. For example, Ten and coworkers synthesized lignin nanotubes in a sacrificial alumina membrane template using the lignins extracted from different extraction agents50. Compared with other extraction agents (phosphoric acid, sulfuric acid, and thioglycolic acid)50, the lignin nanotubes synthesized from the NaOH-extracted lignin possess the shortest length endowing the lignin nanotube with high penetration into nucleus and high gene transfection efficiency. In addition to lignin nanotubes, lignosulfate was also functionalized with allyl groups to generate nanoparticles. via a thiol-ene radical reaction51, and alkyl lignin was quaternized and mixed with sodium dodecyl benzenesulfonate to form the self-assembled micelles52. By these modifications of lignin, these lignin-based carriers possess a pH-sensitive function for controlled release applications. Moreover, several simple processes with no chemical modifications were developed to obtain pure lignin nanoparticles individually53-54. Lievonen and coworkers used water as a nonsolvent to limit the freedom of lignin chains in solution and encapsulate the hydrophobic region within the forming nanoparticles53. Compared to the nanoparticles prepared from other methods55-57, the nanoparticles made by Lievonen’s method have carboxyl and phenolic hydroxyl groups to enhance the formation of electrical double layers53, indicating that the nanoparticles through electrical doublelayer repulsion, have good stability and dispersion in water for over two months. Additionally, Frangville generated low-sulfonated lignin nanoparticles by using aqueous solutions with different pH values for precipitation58. The phenolic hydroxyl groups and carboxyl groups of lignin nanoparticles are pH-stable only when the pH value is lower than five. Following an increase in the pH (>5), the lignin nanoparticles undergo reversible dissolution, showing that the nanoparticles undergo a controlled release function for drug delivery (Figure 2a). Additionally, Figueiredo et al. further synthesized iron-complexed lignin nanoparticles by modifying the phenolic groups of lignin58. The modified lignin nanoparticles with dual functions enabled the specific targeting of cancer cells through application of a magnetic field and controlled drug release through the sensing of the pH variations within cancer cells. These cases indicate that lignin has a potential as a carrier in the drug delivery/controlled release field. However, lignin has a highly irregularly branched phenolic structure that consists of monolignols and various alcohol units linked via an aliphatic ether and aromatic bonds59. These inhomogeneity and complexity structures add additional challenges for 7 ACS Paragon Plus Environment

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the isolation, conversion, valorization and others of lignin resources60-61. For example, these structural characteristics limit the dispersibility and drug entrapment of pure lignin nanoparticles with preferred spheres62. Thus, the effective methods warrant further development to solve these current challenges in the future. Cellulose and its derivatives are frequently and broadly used in industrialized pharmaceutical products with different purposes63, especially in oral controlled release64-65. One cellulose derivative, cellulose acetate phthalate (CAP), was first used to control the release of drugs because its pH-sensitive solubility could be regulated through the degree of substitution by phthalic anhydride 66. Additionally, cellulose, as an enzyme-triggered material, was used to modify the surface of mesoporous silica nanoparticles via esterification67 (Figure 2b). Subsequently, the release of drugs could be achieved by using cellulases to digest the cellulose and acid hydrolysis to rupture the ester linkages. Additionally, a nanostructured cellulose, nanocellulose, is a novel biomass material with high stability and low cytotoxicity applied in smart controlled release68. Due to the nanoscaled structure of cellulose fibrils, it provides a high surface area-to-volume ratio for drug binding on nanocellulose fibrils69. Moreover, the abundant functional groups such as OH group on nanocellulose fibrils endow nanocellulose with many active moieties to make the physical or chemical modifications70. Through the modifications, the nanocellulose-based materials with specific functions could be used as drug carriers for controlled release. For example, Saïdi and coworkers in situ synthesized poly(N-methacryloyl glycine) within the nanocellulose network to develop a pH-sensitive nanocellulose-based membrane with potential application in both oral and transdermal drug delivery71. As is well known, chitosan is a biodegradable and biocompatible polysaccharide. Unlike the sustainable biomass materials highlighted above, chitosan is a biomass material obtained from crustacean raw materials and contains an abundance of amine groups. These amine residues on the chitosan backbone demonstrate protonation behavior that contributes to forming positive charges at low pH values (below pH 6.5), endowing chitosan with pH sensitivity. Based on the positive charge and pH-sensitive feature, chitosan as a versatile biomass material has attracted increasing attention from scientists for the development of chitosan-based drug-delivery systems72-74. In terms of drug delivery, the considerable positive charge of chitosan binds efficiently to cells because of the abundant anionic phospholipid phosphatidylserine present in cellular membranes. Therefore, many chitosan- and chitosan derivative-based cargos were thoroughly investigated and applied in oral/mucosal drug delivery in early studies75-76. Additionally, advanced nanoparticle or nanocomposite systems were fabricated based on the polycationic and pH-sensitive features of chitosan to encapsulate drugs and control their release for more applications74,

77-79.

He et al. recently developed



nanoparticles consisting of chitosan, tripolyphosphate, and insulin through a polyelectrolyte complex coacervation technique80, which prevented the degradation of insulin in the stomach. Subsequently, the deprotonation of the amine groups in the intestinal environment resulted in the disintegration of the nanoparticles; thus, the chitosan nanoparticles controlled the release of insulin, thereby enhancing the intestinal epithelium permeability of insulin and significantly controlling the blood sugar level in a rat model with type I diabetes. Another chitosan-based delivery microgel was designed to respond to both glucose and pH changes81 (Figure 2c). The microgel mainly comprised a glucose-sensitive glucose oxidase (GOx) and pH-sensitive chitosan. When GOx sensed a high level of glucose, the oxidation of glucose resulted in a lowering of the pH, leading to the swelling of the chitosan microgel by the protonation of the amine groups and induction of the release of insulin. In addition to diabetes, chitosan-based systems have also been commonly used in cancer therapy studies82-83. Ro and coworkers created pluronic 127-linked chitosan nanoparticles with additional surfacedecorated chitosan to encapsulate doxorubicin, a common anti-cancer drug84. Based on the thermosensitive properties of pluronic 127, doxorubicin was shrunk in the nanoparticles at the temperature of the human body (Figure 2d-i). Subsequently, chitosan contributed two functions in this smart release system: (1) targeting a specific cellular surface receptor on the cancer stem-like cells (not expressed in normal cells) (Figure 2d-ii) and (2) degrading or expanding the nanoparticle structure and then releasing doxorubicin within the cells after cellular uptake. Their results showed that smart delivery systems can significantly improve the effects of drug delivery and reduce drug accumulation in normal organs, indicating that this design is potentially useful in chemotherapy. In the drug delivery and controlled release fields, the pH-sensitive feature of polysaccharide is a common function that has been used in studies. Herein, although we mentioned the utilization of only the pH-sensitive properties of polysaccharide in drug-delivery applications, other sensitive properties, such as thermosensitivity85-86, are worth extending to drug delivery applications. 2.3. Tissue engineering Tissue engineering is a multidisciplinary science involving the interactions among biomaterials, cells, and exogenous/endogenous factors in the culture environment, causing tissue engineering to become a popular research topic in the biomedical field. The application of two dimensional (2D) substrates or 3D scaffolds as biomaterials to regulate cellular behaviors, such as proliferation, differentiation, and cellular arrangements, or to fabricate the specific structures of cells as artificial organs, has been widely reported74, 87-88. To mimic biological structures, the properties of biomaterials, 9 ACS Paragon Plus Environment

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including the sensitivity, porosity, mechanical properties, and swelling, must fit the requirements of real tissues in the human body89-91. For instance, Levental et al. reported that the elastic moduli of organs are in the range of 17 Pa to 310 Mpa (i.e., fat to tendons)92, indicating that fabricating constructs similar to the original tissues is important to regulate cell behavior. Some sustainable biomass materials are saccharide unit-linked by glycosidic bonds, similar to some of the components of the human body. Moreover, linear/branched morphologies and homo/heteroglycan structures endow biomass materials with tailorable properties as versatile biomaterials for different purposes in tissue engineering applications3, 93. Chitosan is a well-known and popular biomass material used in biomedical applications. The structure of chitosan contains one of the components of the ECM, glycosaminoglycan, thereby allowing chitosan to interact with other ECM components to regulate cell-cell and cell-substrate adhesion. For example, the pH sensitivity of chitosan has been reported to be used for cell selection by performing the fibronectin adsorption/detachment of chitosan under different pH conditions, regulating various cellular adhesive abilities on chitosan94. Additionally, the positive charge of chitosanbased materials also provides an antimicrobial property by disrupting the integrity of the bacterial cell membrane. This antimicrobial feature has increasingly motivated researchers to use chitosan as a possible implant in tissue engineering95. Nonetheless, the pKa of chitosan (approximately 6.5) limits its solubility under natural pH conditions, and the abundance of lysozymes in the body that can cleave the β-(1,4) glycosidic linkages of chitosan chains causes chitosan to quickly and easily degrade in vivo 96. These issues inevitably restrict the applications of chitosan in tissue engineering. Fortunately, chitosan contains amine and carboxymethyl side groups, which provide active sites for modification with other materials to overcome the abovementioned limitations, even endowing chitosan with new functions. For instance, Hu et al. developed a photocrosslinkable chitosan derivative by modifying glycol chitosan with a methacrylate functional group. As a result of the curing process, the degradation rate of the chitosan hydrogel decreased, supporting the proliferation of encapsulated chondrocytes, deposition of ECM and enhanced repair of damaged cartilage97 (Figure 3a). In addition to small molecules, chitosan was further modified with other polymers such as poly(ethylene glycol) to obtain an injectable hydrogel to repair defects in the central nervous system98 or by collagen as a biomimetic skin for healing defects in the skin99. Cellulose possesses a hierarchical structure of natural fibers and a high content of hydroxyl groups, providing unique strength, high performance, and high affinity for water. The unique structure and easily machinable/modifiable property of cellulose offer a good match of mechanical properties with soft and hard tissues100-101. 10 ACS Paragon Plus Environment


Additionally, the high water affinity endows cellulose with hydrogel-like properties as a 3D scaffold for host cells102 (Figure 3b-i). As 3D engineered tissue constructs scaffolds made from fibrous cellulose, they could also provide the appropriate porous structures for oxygen/nutrient exchanges, cell growth, and cell transient effects102. In addition to cell culture, some tissue structures such as bone possess a porous and crystalline morphology, allowing the strength of the tissues to be reinforced103. These features showed that cellulose with a fibrous and high hierarchical structure is suitable for use in bone tissue engineering104. Therefore, based on the abovementioned information, cellulose-based materials are broadly used not only as pure materials but also as additives to fabricate 3D porous constructs105-106(Figure 3b-ii). Furthermore, combining a modest content of cellulose-based materials with various manufacturing processes (e.g., freeze-drying107, electrospinning108, and lithography106) could introduce tailorable mechanical properties and various biomimetic topographical features in 3D cellulose-based architectures to regulate the alignment, behavior, or regeneration of cells/stem cells. Next, broadly speaking, silk fibroin is one type of sustainable biomass material derived from silkworms, spiders, and other insects109. Silk fibroin mostly consists of poly glycine-alanine- and poly alanine-based repeating units, similar to the structure of the other amino acid-based material, collagen, strongly contributing to the movement of the amorphous regions and β-sheet configuration110. Generally, the widely used physical properties of silk fibroin are both the extensibility and high tensile strength111. Maueny and coworkers utilized the extensibility and high tensile strength of silk to fabricate a bladder alternative. Implantation of this alternative into a murine bladder augmentation model showed that the gel-spun, silk-based matrix provided a superior alternative to allowing urothelial and smooth muscle regeneration and significantly increased the capacity of the bladder112. Additionally, Hu et al. developed a silk-mixed composite as a bone substitute113. In their study, the addition of silk enhanced the elastic modulus 2-3 times more than that of the composite without silk. Meanwhile, osteoblastlike cells on the silk-based bone substitutes also exhibited strong adhesion, good spreading, and a high proliferation ability. Moreover, Kaplan and his group first developed a 3D silk ECM-based gel as an in vitro model for tissue-level functional assessment (Figure 3c). The tunable mechanics of silk enabled the gel to maintain brainlike elasticity and slow the degradation, providing a suitable cortical niche to replicate the neuronal network and electrophysiological functions and examine the response to traumatic brain injury114. In addition to reinforcing the mechanics, the amino acid-based silk fibroin as a biomaterial can prevent chronic inflammation115. Therefore, silk fibroin gel was also used as an implant in the damaged brain of a mouse with Alzheimer’s disease, indicating that silk can reduce the inflammation effect, produce a high survival 11 ACS Paragon Plus Environment

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rate (exceeding 90%), and coexist with the neuronal circuit related to learning/memory mechanisms and sensorimotor coordination116. Gelatin is a denatured collagen that retains cell-binding moieties such as RGD and is a potential biomimetic ECM material. However, the gelation temperature of gelatin is approximately 30 ℃; thus, pure gelatin constructs easily degrade in the culture environment (37 ℃) while incubating with cells. Amine side groups offer various methods to chemically modify gelatin. To overcome the abovementioned challenge, gelatin is modified by linking methacrylate groups to its amine-containing groups to produce the photopolymerizable material gelatin methylacrylate (GelMA), which is stable at 37 ℃117. GelMA has been used for various applications because of its hydration and mechanical properties118. Notably, the tunable mechanical properties can be regulated from 5 kPa to 30 kPa by controlling the degree of methacrylation and gel concentration that is used to form cell-laden materials119. Based on the relationship between the methacrylation degree and mechanical properties, Khademhosseini and his team microengineered microhybrid cardiac constructs using a cardiac-like modulus (approximately 10-45 kPa) by mixing a GelMA hydrogel with a medium degree of methacrylation with conductive materials such as reduced graphene oxide or gold nanorods 120-121. The cardiac cells in these engineered cardiac constructs showed not only significant extension morphologies but also good electrophysiological properties (Figure 3d). Moreover, in addition to cardiac tissue engineering, GelMA polymers with versatile functions have also achieved desirable applications in bone tissue engineering. After photocrosslinking, the GelMA hydrogel exhibits good mechanical robustness similar to that of bone. Importantly, the formation of an internal network morphology in the GelMA hydrogel provides a highly porous structure, mimicking the sponge bone structure and enhancing osteoblast differentiation of stem cells and bone formation122. The materials applied as scaffolds in tissue engineering require modest mechanical properties, good stability, and biofunctions for cells in long-term cultures. Sustainable biomass materials include amino acid-, glycosaminoglycan-, and saccharide-based biomaterials with different functional side groups, crystallinities, or configurations. These features offer sustainable biomass materials that can be broadly used to fabricate ideal scaffolds to regulate cellular behavior, imparting bioactive properties in engineered tissue, or repairing damaged tissue. 2.4. Biosensing In clinical diagnosis, biomarkers such as urea, glucose, and pH are important biological indexes that indicate the functions of organs in the human body. For example, urea and pH examinations are regularly utilized in clinical diagnosis to evaluate the functions of the kidneys. Biosensors are considered analytical devices that can detect 12 ACS Paragon Plus Environment


biomarkers related to target analytes or biological environment changes and then convert the changes into real-time measurable signals. Compared with the current benchtop analysis methods, biosensors provide a low-cost, highly selective/sensitive, real-time, and miniaturized method to measure the changes in biomarkers. Basically, some active biomolecules, such as enzymes, are widely immobilized on substrates as recognition elements to detect biomarkers. To maintain the activities of these biomolecules on the substrates, the materials applied as biosensors should satisfy the following basic requirements: (1) provide a sufficient number of active sites to immobilize a large number of molecules, (2) be fabricated by a gentle process to avoid the inactivation of the biomolecules, (3) be compatible with real samples such as blood without pretreatment, and (4) exhibit a high selectivity/sensitivity for the targeted biomarkers. As mentioned earlier in this article, alginate is an unbranched biomass polysaccharide with an egg-box structure, enabling it to form physical crosslinking bonds with divalent ions such as Ca2+. Via the egg-box structure, alginate has been shown to be feasible for use in the detection of urea and microorganisms in previous studies123-124. These studies provided concepts for fabricating alginate bead biosensors by physical or chemical cross-linking methods, which encapsulated fluorescencelabeled biomolecules in the beads, providing the ability to sense the pH/urea concentration or perform bacterial quorum sensing. Subsequently, these biosensors generated changes in the fluorescence intensity according to changes in the pH/urea concentration or number of bacteria. In addition to detection based on the fluorescence intensity, electrochemical methods offer a rapid and efficient technique for detection. Therefore, transducers or electrodes with well conductivity are considered as biosensors to capture the changes in electrochemical signals. To increase the conductivity, nanoparticles such as carbon-based nanotubes, graphene variants, metallic and metal oxides, and others are usually disposed on substrates as the transducers or electrodes via electrostatic interaction and π–π stacking125. However, there are still some challenges: (1) the disposed nanoparticle-based films are unstable, having the risk of delamination from substrates and shortening the lifetime of biosensors126; (2) unmodified nanoparticle-based electrodes have poor selectivity, sensitivity and other factors for the measurement of biomarkers, and lacking suitable functional groups limits the modification of electrodes127. Therefore, sustainable biomass materials show potential for applications as hybrid biosensors for the detection of biomolecules in biological samples128. For example, the harsh experimental conditions easily disrupt the activity and selectivity of enzymes on biosensor surfaces during the immobilization processes. As abovementioned, alginate can crosslink with Ca2+ to form a gel under mild environments (i.e., neutral pH value and without requiring 13 ACS Paragon Plus Environment

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irradiation or temperature), indicating that alginate has the potential to maintain the integrity, activity, and selectivity of enzymes129. Therefore, Marquez and coworkers directly mixed alginate with horseradish peroxidase and glucose oxidase to form an enzyme-laden barrier on a gold transducer via electrodeposited interactions, enhancing the stability and selectivity of the enzymes. Meanwhile, the barrier formed by the alginate gel protects the gold transducer from biofouling, endowing the gold transducer with the ability to be reused after the removal and re-electrodeposition of alginate gel to entrap glucose in whole-blood samples130. Additionally, gelatin- and chitosan-based hybrid biosensors have been grafted on electrodes as DNA biosensors based on their high DNA-binding affinities to improve the specific sensing abilities of biosensors131132. Recently, 3D porous hydrogels have attracted increasing attention as biosensors due to their large surface area133. In the fabrication of 3D biosensors, the egg-box structure of alginate provides a simple operation process to build 3D cryogels in micropipette tips. Fatoni and coworker placed alginate solution with glucose oxidase in a micropipette tip and then added calcium chloride into the tip to form alginate hydrogel134. Subsequently, the alginate hydrogel was kept in the freezer at -20 ℃ and thawed in the refrigerator at 4℃ to make the alginate cryogel. During the freeze-thaw process, the formation and melting of ice crystals in the alginate cryogel create the interconnected pores135 so that the formed alginate cryogels have a large surface area, enhancing the sensitivity and stability of the biosensor performance in the detection of glucose134 (Figure 4a). Moreover, the freeze-thaw method was applied in the fabrication of 3D porous chitosan-based sensors123. Additionally, the hydroxyl and amine groups on chitosan could form coordination bonds with metal ions such Co or Pt136-137 to stabilize the skeletons of 3D porous chitosan-based constructs, prevent gel dissolution, and allow a high density of enzyme to be deposited to increase the sensitivity of biosensors. Next, based on the catalytic reactions of enzymes, the chromogenic/electrical signal changes caused by chemiluminescent molecules123 (Figure 4b) or biomarkers such cholesterol and glucose in blood samples137-138 could be measured (Figure 4c). In the last decade, advanced paper-based biosensors have provided the ability to fabricate flexible, miniaturized, economical, and disposable biosensors. Paper has a multilayer structure with internal networks consisting of cellulose fibers. In terms of paper-based biosensors, cellulose is a popular candidate to make paper-based analytical devices for point-of-care applications because of its high modulus, low thermal expansion coefficient and other properties. Moreover, the high content of hydroxyl groups on the backbone of cellulose endows it with highly bioactive moieties, enabling easy modification by chemical compounds and subsequent fabrication of biosensors with various sensing functionalities139. For example, esterase is abundant in the body 14 ACS Paragon Plus Environment


and participates in various biochemical reactions in physiological environments; for in vitro and in vivo diagnostics, Derikvand and coworkers developed a reverse cellulose paper with high sensitivity and specific activity for esterase by using copper(I)catalyzed azide-alkyne cycloaddition (named “click chemistry”) to bind a liberated biomolecule-chromophore diester to xyloglucan on cellulose140 (Figure 4d). Subsequently, the chromophore became emissive after removal of the liberated biomolecules via reaction with esterase. Notably, the reverse method of anchoring a chromophore on a cellulose paper biosensor provides a way to address the problem of chromophore diffusion that results in signal attenuation and potential toxicity after cleavage. Biosensors provide the ability to detect minuscule but vital changes in the biological environment and then provide the necessary information for diagnostics. For their easy use, portability and miniaturization are essential for the fabrication of biosensors such as paper-based biosensors. In addition to miniaturization, biosensors also need versatile functions, such as high selectivity and sensitivity (e.g., enzyme, glucose, electrons), to capture the changes in signals or even directly entrap microorganisms or cells. Here, the application of sustainable biomass materials in the fabrication of miniaturized biosensors has been shown to be feasible, and these materials possess various bioactive moieties for different modifications, indicating that biomass-based biosensors provide a new strategy to further build the next generation of biosensors for various applications. 3. Conclusion and perspective Sustainable biomass materials derived from renewable resources, such as the raw materials from agricultural processes, ocean plants, and animal residues, have emerged as attractive alternatives to traditional petrochemical polymers to develop new materials. Using the products from sustainable biomass materials contributes considerably to the economic viability and provides a cleaner environment. Therefore, sustainable material-derived products have been broadly applied in energy storage, packaging, and even biomedicine. In general, most biomass materials contain saccharide repeat units, which offer crystalline regions that contribute to improving the mechanical properties. Furthermore, some biomass materials with body-like components, such as amino acid repeat units, also have good biocompatibility and biodegradability for biomedical uses. Moreover, saccharide- and amino acid-based structures possess different functional groups (e.g., OH, -COOH, -NH2) and backbone configurations (e.g., linear, branched, folded). These features as bioactive moieties allow the physical crosslinking of biomass materials with metal ions/other polymers and chemical grafting of biomolecules, endowing the 15 ACS Paragon Plus Environment

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modified biomass materials with versatile functions (e.g., printability, selectivity, and sensitivity) for various purposes in biomedical applications. However, although sustainable resources provide an endless source to produce biomass materials, several ongoing limitations make it necessary to resolve the current challenges for use in biomedical applications. First, the solubility of some biomass materials limits the use in applications. For example, although chitosan has shown its well biocompatibility, the property of chitosan, dissolved in dilute acid aqueous solution, limits the direct use in the encapsulation of cells141-142. Second, the purity and sources of biomass materials are concerns for use in biomedical applications. The impurities and sources from animals in biomass materials pose a potential risk because they can trigger undesired immunoreactions. Third, some natural biomass materials, such as alginate, chitosan, or gelatin, lack suitable mechanical property or stability for different applications despite their well biocompatibilities143. For example, the compressive modulus of freeze-dried chitosan sponges is in the 8- to 12-kPa range, which is not suitable for use in bone-tissue regeneration144. Therefore, these biomass materials require further modification or blend with other materials to improve their mechanical properties. Fourth biomass materials are derived from various raw materials, which cause biomass materials to have various components or structures, and some biomass materials consist of complex units and branched structures. These issues lead to undefined heterostructures and difficult operational properties (e.g., solubility or modification) for use in biomedical applications. Fifth, biomass materials exhibit poor electrical conductivity. In some cases of biosensors, biomass materials need to mixed with other conductive materials such as graphene145 or gold nanoparticle146 to enhance their sensitivities to detect the minuscule changes in electrochemical signals. Therefore, these current limitations are still needed to be further investigated and resolved for future biomedical applications. Sustainable biomass materials are derived from natural materials with various components, such as saccharide and amino acids, showing that biomass-based products are suitable candidates for application in the biomedical field. Here, although we introduced only a few of the biomass materials that are widely used in biomedical applications, many current biomass materials also possess properties that give them potential for use as biomaterials. For example, lignin and its derivatives can bind to their receptors on cell membranes and further participate in the cell signaling pathway to regulate the specific differentiation of stem cells147. This result also implies that lignin has potential for application as a drug delivery carrier or even as a drug. Moreover, in addition to using the properties of one biomass material, the various features of multiple biomass materials could be combined to develop novel systems, such as biosensor-based smart drug delivery systems. Therefore, through the introduction of 16 ACS Paragon Plus Environment


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Figures

Figure 1. (a) The images of a construct printed by a cellulose nanofibril-based hydrogel ink. (Reprinted with permission from [31] Copyright (2016) John Wiley & Sons.) (b) The effect of cellulose on printed structures. Methylcellulose mixed in alginate ink can prevent the collapse of printed fibers and constructs. (Reprinted with permission from [30] Copyright (2017) American Chemical Society.) (c) The illustration and images present the egg-box effect of alginate and the complex vessel, heart, and brain structures printed by using pure alginate bioink through the egg-box effect. (Reprinted with 31 ACS Paragon Plus Environment

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permissions from [34] Copyright (2015) Royal Society of Chemistry and [35] Copyright (2015) American Association for the Advancement of Science.) (d) The schematic illustration, fluorescent and optical images of gelatin-based materials printed vascular networks. Confocal image shows human umbilical vein endothelial cells lining the printed vascular channel walls. (Reprinted with permission from [40] Copyright (2014) John Wiley & Sons.)




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Figure 2. (a) The preparation of pH-sensitivity lignin-based nanoparticles (Reprinted with permission from [58] Copyright (2012) John Wiley & Sons.) (b) The synthesis of pH- and enzyme-sensitive cellulose-modified mesporous silica nanoparticles for doxorubicin delivery (Reprinted with permissions from [67] Copyright (2016) Royal Society of Chemistry.) (c) The schematic of dual glucose- and pH-response chitosan cargos entrapping GOx and model protein drugs. (Reprinted with permission from [81] Copyright (2017) American Chemical Society.) (d) (i) The synthesis of doxorubicinencapsulated chitosan nanoparticles by using an oil-in-water method. (ii) The controlled release mechanism of chitosan nanoparticles with high selectivity to target cancer cells and smart release in cancer cells. (Reprinted with permission from [84] Copyright (2015) American Chemical Society.)



Figure 3. (a) The schematic of fabricating cartilage cell-laden chitosan/collagen II scaffolds. The images show cells with a well adhesion in this chitosan hydrogel and a well binding to collagen through integrin α10, and the cell-laden scaffold with an ability to promote cartilage regeneration. (Reprinted with permission from [97] Copyright (2014) American Chemical Society.) (b) (i) The SEM images of porous structure in cellulose-based hydrogels and morphology of cells growing in this hydrogel. (Reprinted with permission from [102] Copyright (2015) John Wiley & Sons.) (ii) The photograph and SEM image of 3D large-scale cellulose cubic scaffold fabricated by using layered micromirror lithographic technique. (Reprinted with permission from [106] Copyright (2015) John Wiley & Sons.) (c) The design and images of silk-based six laminar layers of cortex construct (i and iv), unit module with gray matter and white 35 ACS Paragon Plus Environment

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matter (ii and v), and supporting moieties for axon connection (iii and vi). (Reprinted with permission from [114] Copyright (2014) National Academy of Sciences.) (d) The preparation of GelMA/gold nanorod mixture and the fabrication of cardiac cell-laden micro-constructs. The fluorescent image shows the cardiac cells in GelMA constructs with well extension morphology and expression of cardiac cell markers. (Reprinted with permission from [121] Copyright (2017) John Wiley & Sons.)



Figure 4. (a) The preparation of glucose-sensitive 3D alginate cryogel sensors. (Reprinted with permission from [134] Copyright (2016) IOP publishing.) (b) The illustration of catalyst-laden chitosan hydrogel and the sensing mechanism of chitosan biosensors. (Reprinted with permission from [123] Copyright (2015) American 37 ACS Paragon Plus Environment

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Chemical Society.) (c) The schematic illustrations and SEM images of glucose-senstive 3D chitosan fibrous sensors. (Reprinted with permission from [138] Copyright (2015) John Wiley & Sons.) (d) The design of cellulose-based enzyme sensor, showing that chromogen or fluorogen can bright fast after enzyme breaking the linkage between biomolecule and chromogen/fluorogen and then released low toxicity biomolecule can be degradable. (Reprinted with permission from [140] Copyright (2016) American Chemical Society.)



For Table of Contents Use Only

Title: Sustainable Biomass Materials for Biomedical Applications Author: Yi-Chen Ethan Li


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Sustainable Biomass Materials for Biomedical Applications - ACS

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