Biomacromolecules for Tissue Engineering - ACS Publications

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Perspective

Biomacromolecules for Tissue Engineering: Emerging Biomimetic Strategies Jason Liwei Guo, Yu Seon Kim, and Antonios G. Mikos Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.9b00792 • Publication Date (Web): 08 Jul 2019 Downloaded from pubs.acs.org on July 18, 2019

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Biomacromolecules

Biomacromolecules for Tissue Engineering: Emerging Biomimetic Strategies Jason L. Guo 1†, Yu Seon Kim 1†, Antonios G. Mikos 1*. 1Department

of Bioengineering, Rice University, 6500 Main Street, Houston, TX 77030 †These

authors contributed equally.

KEYWORDS: biomimetic, bioconjugation, bioinspired, shear thinning, 3D printing, spatiotemporal, stimuli-responsive ABSTRACT Biomacromolecules used for tissue engineering must possess either inherent biochemical cues for tissue regeneration or be chemically modified to incorporate bioactive, tissue-specific moieties. To this end, many strategies have emerged recently in the field to both utilize novel bioinspired macromolecules for tissue engineering and apply bioconjugation strategies for the functionalization of biomacromolecules with tissue-specific cues and other biological properties of interest. Furthermore, biomacromolecules have been processed into more highly biomimetic and clinically deliverable scaffold and hydrogel systems using 3D printing and the fabrication of in situ forming hydrogels, respectively. To support these advances, tissue engineers have also pursued greater spatiotemporal control over macromolecular bioactivity and the modulation of scaffold and hydrogel properties in response to both physiological and external stimuli. This perspective thus highlights a few notable advances and techniques in the usage of biomacromolecules

for

tissue

engineering

applications,

including

new

bioinspired

* Corresponding author: Mikos, Antonios G. (telephone: 713-348-5355, fax: 713-3484244, email: [email protected]) ACS Paragon Plus Environment

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macromolecules, advanced hydrogel and scaffold fabrication techniques, and spatiotemporal control over biomacromolecule constructs.

1. INTRODUCTION Tissue engineering strategies leverage biomacromolecules – by this perspective’s definition, large and/or polymeric molecules utilized in a biological context – in the form of fabricated scaffolds or hydrogels for the delivery of signaling molecules and/or cell populations. With the usage of various synthetic and natural biomacromolecules for tissue engineering, an underlying theme is the pursuit of biomimicry – replicating the biochemical, physical, and mechanical properties of native tissue. Several emerging practices in biomacromolecule synthesis and modification have improved the ability of synthetic and biologically derived polymers to provide biochemical cues for tissue development. Furthermore, advanced scaffold fabrication techniques have enabled the creation of high-fidelity anisotropic scaffolds that recapitulate the heterogeneous distributions of biomolecules in native tissue. The development of in situ forming hydrogels has also enabled more facile and non-invasive delivery of biomacromolecule systems, improving utility for potential clinical delivery scenarios. Alongside these advances, tissue engineers have pursued greater spatiotemporal control of bioactivity and the properties of fabricated constructs, in order to mimic the complex biochemical milieu present during native tissue development. This perspective focuses on recent developments in the aforementioned areas, providing analysis of several emerging techniques for further investigation as well as suggested areas of future application in tissue engineering. 2. BIOINSPIRED AND BIOACTIVE MACROMOLECULES

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Tissue engineering scaffolds must possess tissue-specific bioactivity to produce tissue repair of the desired phenotype. Under the traditional paradigm of tissue engineering, bioactivity is provided by the controlled release of growth factors or other signaling molecules. More recently, however, many strategies have pursued the creation of scaffolds using macromolecules that possess inherent bioactivity for the application of interest. To this end, various bioinspired synthetic materials and other types of macromolecules derived from biological systems have been investigated extensively. Another method of providing tissue-specific bioactivity has been to chemically functionalize various biomacromolecules with tissue-specific cues using methods from the field of bioconjugation, which utilizes highly specific linker chemistries to bind proteins and other tissuespecific compounds to polymers.1 The following discussion highlights some prominent approaches for both the design of tissue-specific biomacromolecules as well as the biofunctionalization of macromolecules using bioconjugation techniques. 2.1. Bioinspired Design of Macromolecules The term ‘bioinspired’ indicates that specific motifs or designs found on the macromolecule have been borrowed from those present in nature. For tissue engineering applications, motifs can include repeating patterns found in natural polymers, strongly bioactive moieties of glycosaminoglycans (GAGs) or structural proteins such as collagen, and the binding sites of tissue-specific enzymes. The creation of bioinspired macromolecules often involves a modular approach in which one or more of these motifs is incorporated into the macromolecule during chemical synthesis. One platform that allows for the reproduction of these motifs is solid-phase peptide synthesis. In particular, the synthesis of peptide amphiphiles (PA) which can undergo self-assembly has been an area of great interest for tissue engineers as a tool to fabricate soft hydrogels. Some of the recent works that highlight the usage of PA in tissue engineering can be found in recent reviews.2,3 The


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modular nature of PA design allows for the synthesis of self-assembled hydrogels that possess inherent bioactivity specific to the type of peptide sequence that has been incorporated.4 For instance, PAs incorporating laminin-mimetic sequences have been shown to induce neural differentiation of mesenchymal stem cells.5 Structural elements from macromolecules such as GAGs can also be expressed on the surface of PAs.6,7 By conjugating sulfated monosaccharides at the termini of individual PAs, self-assembled nanostructures that can bind heparin-binding growth factors such as bone morphogenetic protein-2 (BMP-2) have been successfully synthesized.6 Throughout the process of designing bioactive PAs, one must consider not only how such modification can impact self-assembly, but also whether these surface moieties can interact with biomolecules of interest to induce a biological response from the host tissue. One of the disadvantages of PAs is their weak mechanical properties, which presents a challenge for use as a standalone biomacromolecule for fabricating hydrogels. This property has been partially overcome by using PAs as a supplement to other biomacromolecules in bulk hydrogels8 and by chemically crosslinking the peptides to a secondary polymeric network.9 Naturally derived biomacromolecules have also been utilized for the fabrication of biomimetic scaffolds in recent literature. One such biomacromolecule that has been gaining increasing attention is silk fibroin (SF), which is a fibrous protein isolated most often from cocoons of silk moths.10 Isolation of SF from silk moth cocoons, known as degumming, involves multiple steps, and the quality of purified SF such as molecular weight, charge distribution, and ultimately fiber stiffness, can be modulated by adjusting certain variables in the process.11 SF has shown to support the adhesion and proliferation of mesenchymal stem cells on the fiber surface12 and act as a template for mineralization of nanoscale HA crystals.13 Combined with its excellent tensile strength,14 these attributes have resulted in SF being widely processed into various types of


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scaffolds for bone tissue engineering. In most cases, SF is combined with hydroxyapatite,15,16 carboxymethylcellulose,17 or β-tricalcium phosphate18 to further enhance mineralization and osteogenesis. Although most of the applications have involved the regeneration of bone tissue, SF scaffolds can be easily modified to be used for other types of tissues by their combination with biomolecules such as peptides and enzymes that demonstrate tissue-specific bioactivity.19,20 SF can also be fabricated into injectable hydrogels that allow the delivery of cells to the site of interest. This concept has been further explored to develop bioinks for inkjet printing21 and other types of 3D printing (3DP).22 With its inherent bioactivity, favorable mechanical properties and gelation behavior, SF is considered to be a valuable starting biomacromolecule for fabrication of multiple scaffold types targeted toward specific tissues of interest. As with other naturally derived materials, SF suffers from inherent variability with where the raw material is sourced, and how it is processed. As mentioned above, the degumming process involves multiple steps with different variables that are not necessarily universal across the publications that utilize SF. Indeed, physicochemical properties of SF can vary greatly according to the reagent, time, and temperature used during degumming.23 Other factors such as the silkworm cocoon’s species24 as well as age25 have also been shown to affect the properties of the end product. A more thorough investigation into the aforementioned variables and how they affect SF will ensure the consistency and reproducibility of the studies that utilize SF. 2.2. Decellularized Extracellular Matrix Compared to synthetic biomacromolecules and many biologically derived biomacromolecules, decellularized extracellular matrix (dECM) presents a much more potent mixture of tissue-specific biochemical components such as collagen, GAGs, and growth factors,26 and therefore has been shown to have inherent tissue-inductive properties.27 Although methods of tissue decellularization


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have been reported as early as the 1970s,28 dECM has only recently started to gain attention for the fabrication of various types of scaffolds for tissue engineering.29 An overview of these applications can be found in recent reviews.30,31 One application in particular that has been the target of extensive investigation is the use of solubilized dECM, for the development of injectable hydrogels. Upon pepsin digestion, dECM can be solubilized and demonstrates thermoresponsive gelation behavior as the temperature is increased to 37 °C. Synthesized hydrogels from dECM have been shown to support growth and proliferation of encapsulated cells in vitro and exhibit tissue biocompatibility in vivo.32,33 In addition, dECM hydrogels without the addition of cells or bioactive factors have demonstrated regenerative effects in vivo.34,35 Furthermore, dECM hydrogels without the addition of cells or bioactive factors have demonstrated regenerative effects in vivo,36 showing the inherent tissue-specific bioactivity of dECM and its potential as a therapeutic material to be injected into the defect site in a minimally invasive manner. Digested dECM has recently been utilized as a bioink for 3DP applications, although the printability was dependent on the tissue type, specifically their viscosity.37 Efforts to enhance dECM bioinks’ printability involved combining digested dECM with photocrosslinkable polymers such as poly(ethylene glycol) diacrylate38 and gelatin methacrylate,39 adding photoinitiators such as riboflavin into the bioink,40 and directly methacrylating digested dECM.41 Such modifications, however, will bring about inevitable change in the biochemical composition of dECM and could consequently affect scaffold bioactivity and biocompatibility. The biggest challenges in utilizing dECM as a biomacromolecule are the inherent biological variability with tissue samples as well as understanding the effects of different decellularization processes. The composition and quality of the decellularized product have been shown to vary greatly based on tissue source42 and storage conditions.43 This indicates that using the same


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decellularization protocol between studies that use different tissue types or donor species will be unlikely to yield the same result. In addition, different decellularization agents have varied modes of action and affect tissue components accordingly. Care must be taken in choosing decellularization protocol for the specific type of tissue of interest, as different combinations of decellularization methods result in distinct dECM mechanical properties and compositions. For instance, alkaline treatment has been shown to decrease the amount of GAG in the decellularized tissue, which is not suitable for applications in which GAG retention is crucial.30 Extensive efforts have been undertaken by the researchers to summarize the roles of specific decellularization methods and their effects on tissues,44 as well as to categorize methods of decellularization according to tissue type.45 Further understanding of the decellularization process and how it relates to the composition of the decellularized product will be valuable to enhance the reproducibility of studies that utilize dECM as a biomacromolecule for tissue engineering. 2.3. Bioconjugation Bioconjugation involves the usage of highly specific, bioorthogonal reactions to bind a biomolecule of interest to a synthetic or biological polymer, creating a hybrid macromolecule with the biological and physicochemical properties of both components.1 The requirements for these reactions include bioorthogonality, mild and/or aqueous reaction conditions, and high specificity, and further analysis of chemical considerations can be found in existing reviews.1,46,47 Activated ester chemistry utilizing 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and/or Nhydroxysuccinimide (NHS) has traditionally been popular for bioconjugation because of its general adherence to the aforementioned criteria.48 One major pitfall, however, is that EDC, NHS, and the leaving groups produced by their reactions can be cytotoxic above certain concentrations, compromising use for in situ applications in particular.48 Furthermore, the reactivity of the NHS


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and EDC moieties towards amines and carboxylic acids creates significant potential for unwanted linkages and side reactions when used with proteins and longer peptides, in which many amines or carboxylic acids are often present.1 Therefore, other bioconjugation chemistries such as click chemistry, which often presents superior biocompatibility and specificity, have often been pursued for tissue engineering applications in the recent literature.46,49 Click reactions such as the alkyne-azide cycloaddition (AAC) reactions have been popularly used to modify biomacromolecules for tissue engineering due to their high specificity, high yield, and mild reaction conditions.50 Their exploitation of alkyne and azide groups rarely found in a biological context also allows for fully bioorthogonal chemistry. Given these characteristics, AAC has been utilized extensively for biomolecule conjugation49,51 and hydrogel crosslinking.52 Interestingly, several recent applications have utilized AAC for functionalization of biological components like dECM to further enhance their bioactivity. In one case, rat tissues of multiple phenotypes were glycan labeled with azide groups either in vivo or ex vivo, decellularized to produce azide-modified dECM, and conjugated to alkyne-modified heparin to imbue the dECM with antithrombotic properties.51 In another case, C2C12 mouse myoblasts were azide-modified to enable their usage as crosslinkers for alkyne-modified alginate, creating functional hydrogels with adhesive and self-swelling properties produced by the behavior of the cells.52 These novel applications show how bioorthogonal AAC reactions can be used to mix and match biological functionalities by conjugating modular bioactive components. A major pitfall, however, is that in many of these cases it is unclear exactly which proteins and cellular components are being alkyneor azide-modified. One route for investigation could thus be the screening of dECM compositions or cell populations for tissue-specific bioactivity or degree of conversion by the proposed AAC modifications, to assess which components could be bioconjugated or purified, in the case of


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dECM, for an optimal biological response. For the bioconjugation of living cells to polymers, alkyne or azide modification of specific cell surface proteins could also be used to mimic protein interactions seen in tissue development. For instance, the N-cadherin surface protein has been mimicked via peptide-conjugated hydrogels to promote mesenchymal stem cell condensation that, natively, is mediated by N-cadherin during early chondrogenesis.49,53 In addition to the aforementioned static bioconjugations of polymer to biomolecule, recent literature has shown a progression in the usage of dynamic and spatially patterned click binding for tissue engineering. Light-catalyzed AAC and, even more so, light-catalyzed thiol-ene click reactions have emerged as promising means to achieve temporally dynamic and spatially patterned bioconjugation with usability towards various proteins.54–56 In one application, a hydrogel with pendant allyl sulfides provided the substrate for a competitive thiol-ene click reaction with thiolpossessing growth factors including transforming growth factor beta (TGF-β), and UV irradiation was used to swap click-bound proteins with allyl sulfides or vice versa for reversible protein conjugation and de-conjugation.55 The spatial definition and dynamic nature demonstrated by this UV-catalyzed chemistry can thus allow for the creation of bioconjugated hydrogels that mimic the complex biochemical milieu of natively developing tissue. A significant advantage of UV catalysis in this case is its high resolution, which has allowed for thiol-ene click patterned scaffolds with feature resolution as fine as ∼5 μm.57 The prevalence of thiol groups in biomolecules allows for wide applicability of such chemistry, but can also hinder bioorthogonality of in situ reactions, so these considerations should be in mind when selecting an appropriate bioconjugation chemistry. 3. ADVANCED PROCESSING AND FABRICATION METHODS Beyond biomacromolecule selection and chemical modifications, tissue engineers must consider how to process and fabricate these biomacromolecules into hydrogels and scaffolds that (1) can be


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appropriately delivered to the defect site in a clinical scenario and (2) effectively mimic the native architecture, physical properties, and mechanical properties of native tissue. To the first point, much progress has been made for the development of in situ-forming hydrogels with shear thinning properties for the delivery of cell- and biomolecule-encapsulated constructs in a minimally invasive manner. To the second point, the emergence of 3DP techniques have enabled the creation of spatially defined, heterogeneous, and significantly more biomimetic scaffolds compared to those generated by traditional polymer processing and fabrication techniques. The ultimate promise of these relatively new fields of 3DP and bioprinting, which involves 3DP of cells and/or biomolecules,58 is that of tissue- and patient-specific scaffolds which may be designed and customized based on models of the tissue defect itself. 3.1. In Situ Forming Hydrogels In situ forming hydrogels refer to injectable hydrogel systems that can be delivered directly into the tissue defect site as hydrogel precursor solutions and undergo gelation in situ. Various injectable systems have thus far been developed that undergo sol-gel transition via chemical crosslinking and/or physical gelation, as well as in response to physiological stimuli such as temperature and pH.59–61 Given that cells and biomolecules can be easily encapsulated in the hydrogel precursor solutions, these injectable systems have been used extensively in tissue engineering. Shear thinning hydrogels constitute a subset of in situ forming hydrogels that are characterized by reversible non-covalent or physical interactions between the polymer chains or particles, allowing ease of injectable delivery via reversible deformation and recovery of the hydrogel structure.62 Unlike injectable hydrogels that rely on external stimuli to undergo sol-gel transition in situ, the mode of gelation for shear thinning hydrogels is almost entirely dependent on the interaction between the chains or particles and thus, in vivo environmental factors such as


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temperature or pH have a minimal effect on the gelation state of the hydrogel. In addition, their inherent self-healing capabilities and fast shear recovery behavior allow the shear thinning hydrogel to rapidly set upon injection without necessarily relying on external stimuli such as UV irradiation or chemical crosslinking. Polymers modified with adamantane and β-cyclodextrin have been extensively utilized to synthesize hydrogels that have shear thinning capabilities as the hydrophobic guest-host interactions between the two moieties can be broken under shear and then undergo self-healing once the shear is removed (i.e., after being ejected through a syringe needle).63 Physical crosslinking between polymers and charged particles such as silicate nanoplatelets has also been used as a means of providing shear thinning properties to the hydrogel. Nanosilicates are characterized by a platelet-like shape that exhibits anisotropic charge distribution where the particles are anionic on both top and bottom surfaces and cationic on the sides. This makes nanosilicates suitable as a rheology modifier,64 as the electrostatic interaction between the particles allow the suspension to exhibit pseudoplastic behavior. Nanocomposite hydrogels that combine nanosicilates with agarose,65 kappa-carrageenan,86 and chitosan,68 have all shown shear thinning properties. Another class of biomacromolecules that exhibit shear thinning behavior are colloidal suspensions, in which non-covalent interactions between the particles allow the suspension to undergo dynamic formation and disruption of an interparticle network in response to shear. For instance, microgels that are jammed together by centrifugation or vacuum filtration demonstrate shear-thinning and shear-recovery behaviors.69 Simple mixtures of oppositely charged nanoparticles of PLGA70 and gelatin71 also have successfully demonstrated pseudoplastic behavior via electrostatic interactions. This concept has been expanded to fabricate more complex colloidal hydrogels (e.g., surface functionalized nanoparticles, organic-inorganic composite


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particles) with the objective of exhibiting better mechanical properties as well as tissue-specific bioactivity.72 The biggest challenge in relying on non-covalent interactions for the formation of shear thinning hydrogels is the lack of requisite mechanical stiffness for forming complex structures. There have been efforts to utilize these hydrogels for 3DP using the techniques discussed below, and in most cases the biomacromolecules required additional modification to have sufficient mechanical integrity such as by introducing photocrosslinkable groups including methacrylates.73,74 Other efforts to enhance the mechanical properties have involved the formation of double network (DN) hydrogels using two orthogonal noncovalent interactions75 or a combination of noncovalent and covalent crosslinking.76 Unlike traditional DN hydrogels, these exhibited rapid recovery after being placed under high strain conditions, and thus could provide a different approach to developing mechanically stable shear thinning hydrogels that could be used for 3DP. 3.2. 3D Printing of Biomacromolecules 3DP techniques utilize state-of-the-art printer systems to deposit one or more material formulations, referred to as inks, in a spatially defined manner. Bioprinting, in particular, is a subset of 3DP techniques which involves the deposition of bioinks – ink formulations containing cells or biologically derived components – to create more highly biomimetic scaffolds.58 Tissue engineers have successfully printed a plethora of biomacromolecules, with ink formulations that have incorporated growth factors, peptides, glycosaminoglycans, and various synthetic polymers, as summarized in existing reviews.77,78 An area that warrants significant future investigation, however, is the printing of biomacromolecules in multiphasic and gradient distributions to better mimic the complex biochemical microenvironments of native tissue.79 One notable area for improvement is the achievable resolution of biomacromolecule deposition. Light-based techniques


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such as stereolithography, for instance, currently demonstrate a finest achievable resolution of 510µm, while inkjet and extrusion based techniques offer deposition on the finest resolution of about 20µm.58 A frequent constraint in the z resolution of stereolithography is the non-specific polymerization of biomacromolecule hydrogel layers from excess light exposure.78 In recent literature, this limitation was addressed by using biocompatible food dyes as photoabsorbers, limiting crosslinking to highly resolved layers and enabling the fabrication of complex macromolecular features in the z direction.80 Another area for improvement is the maintenance of biomacromolecule bioactivity during the printing process. Growth factors and other proteins are prone to denaturation at high temperatures or in the presence of certain organic solvents, and should often be encapsulated within secondary polymer vessels to provide insulation from the harsh conditions of print methods such as extrusion.81 The development of low temperature printing methods can also help address this limitation. One recent example of low temperature extrusion utilized an ink comprised of PLGA and proteins dissolved together in dimethylsulfoxide (DMSO), producing scaffolds with fibronectin, TGF-β, insulin, and BMP-2 that retained their bioactivity after the evaporation of DMSO.82 The suspension of other growth factors in DMSO and other organic solvents, however, may result in protein denaturation and loss of bioactivity.81 Developing solvent-free, low-temperature printing methods will thus be of interest to avoid the loss of bioactivity for proteins and other biomolecules while continuing to capitalize on the high spatial definition afforded by 3DP techniques. 4. SPATIOTEMPORAL CONTROL OF BIOMACROMOLECULE CONSTRUCTS True biomimicry for tissue engineering must involve not only the spatial patterning of multiple growth factors and biochemical cues as discussed previously, but also temporal control over when these biomacromolecules are presented or released at the site of tissue defect. The pursuit of


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spatiotemporal control represents a significant progression in the regenerative utility of biomacromolecule tissue engineering systems, given that native tissue development involves differential expression of multiple biomacromolecules over time.83 Previous examples in this perspective have illustrated how light-catalyzed click chemistry has been used in some cases for dynamic conjugation and de-conjugation of biomolecules, while 3D printing, on the other hand, has been used for high resolution spatial patterning of biomacromolecules for tissue engineering. The

following

section

serves

to

further

highlight

how

unique,

stimuli-responsive

biomacromolecules and constructs can be used to provide spatiotemporally defined and/or externally controlled biological responses for tissue engineering applications. 4.1. Stimuli-Responsive Biomacromolecules and Constructs Tissue engineered hydrogels and scaffolds can be made stimuli-responsive by incorporating macromolecular components that respond to physical and biochemical stimuli, such as changes in the microenvironment that accompany tissue regeneration. A few examples of these native environmental triggers include pH,84 enzymatic activity,85 and reducing/oxidizing conditions.86 These switches can also include various types of external physical stimuli. For instance, light, magnetic fields,87 and acoustic waves88 have been successfully used to signal a changes in the physicochemical properties of macromolecular hydrogels, leading to their degradation and release of cells and biomolecules. One way that this can be achieved is through the integration of stimuliresponsive crosslinkers in the hydrogel system. This approach has been widely used to fabricate degradable hydrogels, one notable example being PEG hydrogels crosslinked with MMP degradable peptides.85 Altogether, these stimuli-responsive moieties present a toolbox of responses that can be used either alone or in combination to create complex and reactive tissue engineering systems, and more in-depth analyses of stimuli-responsive hydrogels can be found in existing


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reviews.89–91 More recently, this concept has been used to develop logic-gated hydrogels that can exhibit multiple responses depending on how the environmental/external stimuli are combined.92 This was achieved by designing crosslinkers with three different cleavable moieties (redox, enzymatic, light), and depending on how these moieties were linked (e.g. parallel, series, or a combination of the two) the crosslinkers showed different degradation responses.92 Self-assembled peptides, as discussed previously, represent another platform widely used to develop stimuli-responsive hydrogels. By incorporating a segment within the peptide that responds to either environmental or external stimuli, it is possible to fabricate a self-assembled peptide hydrogel that can be triggered to undergo degradation and subsequent release of therapeutics incorporated within the hydrogel. Indeed, various stimuli-responsive hydrogels that are responsive to triggers such as UV irradiation,93 pH,94 and enzymes6 have been successfully fabricated. The fabrication of stimuli-responsive particles can also confer spatiotemporal control over the delivery of cells and growth factor payloads to the site of tissue defect. Precise spatiotemporal control can be achieved by fabricating biomolecule-loaded particles and vesicles that are sensitive toward various external stimuli such as magnetic and electrical fields,95,96 UV and near-infrared irradiation,97,98 and ultrasound excitation.99 For instance, PLGA micro/nanoparticles that only allow for passive diffusion of loaded biomolecules could be modified to degrade and release their payloads in response to an alternating magnetic field via the incorporation of superparamagnetic nanoparticle additives.100 Particles can also be rendered to release their payloads in response to the changing environment within the site of implantation. For instance, macrophage polarization during the initial inflammation stage of tissue regeneration has been exploited to fabricate BMP2-loaded gelatin microspheres that could undergo degradation via inflammatory macrophages and deliver their payloads coordinated with the tissue’s inherent inflammatory response.101 The


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patterning of these delivery vehicles using 3DP techniques could allow for the even higher resolution of spatiotemporal control over growth factor presentation. One of the biggest challenges in the development of stimuli-responsive hydrogels and scaffolds for tissue engineering is the precision or spatial resolution with which the response can be controlled. Conventional scaffold fabrication methods have only allowed for the preparation of bulk, monolithic scaffolds without directionality in stimuli-responsiveness. By using 3DP techniques, spatial gradients of stimuli-responsive biomacromolecules can be introduced within a single scaffold. For instance, a pore-forming hydrogel has been printed as a bioink to control the spatiotemporal delivery of osteogenic and chondrogenic genes to both host and encapsulated cells in vivo.102 Modulation of bioink porosity allowed for adjustment of the rate of gene delivery, while the usage of 3DP techniques allowed for spatial control of where chondrogenic and osteogenic genes were delivered.102 This concept can be expanded upon using multi-material 3D printing systems, which could potentially allow for the fabrication of multi-stimuli responsive scaffolds. Recently the idea of four-dimensional printing has been proposed, which aims to provide printed constructs with the ability to undergo dynamic change in shape over time.103,104 Further advancements in these strategies will thus open up new methods of using distinct internal and external stimuli to precisely modulate biological responses for tissue engineering.

5. CONCLUSIONS AND FUTURE PERSPECTIVES Recent advances in materials science and tissue engineering have improved the ability of biomacromolecules and their fabricated scaffolds to mimic the biochemical, physical, and mechanical properties of native tissue. Natural biomacromolecules such as silk fibroin have gained widespread usage as they have been shown to carry inherent bioactivity that could be harnessed


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and guided toward specific tissues, while self-assembling peptides have also undergone extensive research for use as modular platforms for tissue-specific bioactivity. There has also been a growing trend in utilizing naturally derived bioactive materials such as dECM, which can now be processed into various types of scaffolds. Additionally, bioconjugation and click chemistry techniques have enabled the functionalization of macromolecules with multiple or enhanced biological functionalities. Using dynamic and reversible click chemistry such as light-responsive thiol-ene reactions, tissue engineers have also created constructs with tunable bioactivity. Furthermore, novel biomacromolecule processing and scaffold fabrication techniques have enabled the production of hydrogels and scaffolds that can be more effectively delivered to the site of defect and replicate the heterogeneous microenvironment of native tissue with greater fidelity. Shear thinning hydrogels, for instance, have utilized different types of non-covalent interactions to effect pseudoplastic and self-healing behaviors that enable the facile in situ delivery of cells and biomacromolecule systems. 3DP techniques, on the other hand, have been used to deposit biomacromolecules in highly defined spatial patterns that mimic the complex microenvironment of native tissue. Spatiotemporal control over bioactivity and scaffold properties is another important factor to consider in fabricating a biomimetic tissue engineered construct. For this purpose, stimuliresponsive biomacromolecules have been utilized in recent literature to develop scaffolds and hydrogels with macromolecular components sensitive to physiological stimuli such as pH and enzymatic activity as well as external stimuli such as light and electromagnetic fields. Novel applications of these stimuli-responsive biomacromolecules have included logic-gated hydrogel systems, spatiotemporally controlled delivery of cells and tissue-specific biomolecules, and printing of stimuli-responsive macromolecules.


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Ultimately, the development of more advanced biomacromolecules for tissue engineering will consist of not only the design of novel macromolecular compositions, but also the advancement of biomacromolecule processing and fabrication techniques as well as the pursuit of spatiotemporal control over bioactive properties. The techniques and biomacromolecules discussed in this perspective will continue to play an important role in such endeavors. ACKNOWLEDGMENTS We acknowledge the assistance of Katie J. Hogan in editing and preparing the manuscript. This work was supported by the National Institutes of Health (R01 AR068073 and P41 EB023833). REFERENCES (1)

(2) (3) (4)

(5)

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Table of Contents Graphic: Emerging Trends in Tissue Engineering for the Biomimicry of Native Tissue 204x206mm (96 x 96 DPI)


Biomacromolecules for Tissue Engineering - ACS Publications

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