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A 3D-Bioprinted Multiple Myeloma Model (Adv. Healthcare Mater. 7/2022)
Di Wu, Zongyi Wang, Jun Li, Yan Song, Manuel Everardo Mondragon Perez, Zixuan Wang, Xia Cao, Changliang Cao, Sushila Maharjan, Kenneth C. Anderson, Dharminder Chauhan, Yu Shrike Zhang
doi : 10.1002/adhm.202270034
Volume 11, Issue 7
Injectable Acylhydrazone-Linked RAFT Polymer Hydrogels for Sustained Protein Release and Cell Encapsulation (Adv. Healthcare Mater. 7/2022)
Fang-Yi Lin, Nathan H. Dimmitt, Mariana Moraes de Lima Perini, Jiliang Li, Chien-Chi Lin
doi : 10.1002/adhm.202270035
Polysalicylic Acid Polymer Microparticle Decoys Therapeutically Treat Acute Respiratory Distress Syndrome (Adv. Healthcare Mater. 7/2022)
Emma R. Brannon, William J. Kelley, Michael W. Newstead, Alison L. Banka, Kathryn E. Uhrich, Colleen E. O'Connor, Theodore J. Standiford, Omolola Eniola-Adefeso
doi : 10.1002/adhm.202270037
Template-Enabled Biofabrication of Thick 3D Tissues with Patterned Perfusable Macrochannels (Adv. Healthcare Mater. 7/2022)
Elham Davoodi, Hossein Montazerian, Masoud Zhianmanesh, Reza Abbasgholizadeh, Reihaneh Haghniaz, Avijit Baidya, Homeyra Pourmohammadali, Nasim Annabi, Paul S. Weiss, Ehsan Toyserkani, Ali Khademhosseini
doi : 10.1002/adhm.202270038
Vascularization is key to the prolonged functionality of the organs. Template-assisted bioprinting enables biofabrication of stand-alone thick tissues with complex vascularized networks. In article number 2102123 by Ehsan Toyserkani, Ali Khademhosseini, and co-workers, an indirect printing strategy not only eliminates the need for costly 3D bioprinters, but also allows integration of living cells within the extracellular matrix-mimicking hydrogel matrices.
White Blood Cell Membrane-Coated Nanoparticles: Recent Development and Medical Applications
Dan Wang, Shuyan Wang, Zhidong Zhou, Dean Bai, Qiangzhe Zhang, Xiangzhao Ai, Weiwei Gao, Liangfang Zhang
doi : 10.1002/adhm.202101349
White blood cells (WBCs) are immune cells that play essential roles in critical diseases including cancers, infections, and inflammatory disorders. Their dynamic and diverse functions have inspired the development of WBC membrane-coated nanoparticles (denoted “WBC-NPs�), which are formed by fusing the plasma membranes of WBCs, such as macrophages, neutrophils, T cells, and natural killer cells, onto synthetic nanoparticle cores. Inheriting the entire source cell antigens, WBC-NPs act as source cell decoys and simulate their broad biointerfacing properties with intriguing therapeutic potentials. Herein, the recent development and medical applications of WBC-NPs focusing on four areas, including WBC-NPs as carriers for drug delivery, as countermeasures for biological neutralization, as nanovaccines for immune modulation, and as tools for the isolation of circulating tumor cells and fundamental research is reviewed. Overall, the recent development and studies of WBC-NPs have established the platform as versatile nanotherapeutics and tools with broad medical application potentials.
Engineering Tissues of the Central Nervous System: Interfacing Conductive Biomaterials with Neural Stem/Progenitor Cells
Rebecca D. Bierman-Duquette, Gevick Safarians, Joyce Huang, Bushra Rajput, Jessica Y. Chen, Ze Zhong Wang, Stephanie K. Seidlits
doi : 10.1002/adhm.202101577
Conductive biomaterials provide an important control for engineering neural tissues, where electrical stimulation can potentially direct neural stem/progenitor cell (NS/PC) maturation into functional neuronal networks. It is anticipated that stem cell-based therapies to repair damaged central nervous system (CNS) tissues and ex vivo, “tissue chip� models of the CNS and its pathologies will each benefit from the development of biocompatible, biodegradable, and conductive biomaterials. Here, technological advances in conductive biomaterials are reviewed over the past two decades that may facilitate the development of engineered tissues with integrated physiological and electrical functionalities. First, one briefly introduces NS/PCs of the CNS. Then, the significance of incorporating microenvironmental cues, to which NS/PCs are naturally programmed to respond, into biomaterial scaffolds is discussed with a focus on electrical cues. Next, practical design considerations for conductive biomaterials are discussed followed by a review of studies evaluating how conductive biomaterials can be engineered to control NS/PC behavior by mimicking specific functionalities in the CNS microenvironment. Finally, steps researchers can take to move NS/PC-interfacing, conductive materials closer to clinical translation are discussed.
Hydrogels and Hydrogel Nanocomposites: Enhancing Healthcare through Human and Environmental Treatment
Angela M. Gutierrez, Erin Molly Frazar, Maria Victoria X. Klaus, Pranto Paul, J. Zach Hilt
doi : 10.1002/adhm.202101820
Humans are constantly exposed to exogenous chemicals throughout their life, which can lead to a multitude of negative health impacts. Advanced materials can play a key role in preventing or mitigating these impacts through a wide variety of applications. The tunable properties of hydrogels and hydrogel nanocomposites (e.g., swelling behavior, biocompatibility, stimuli responsiveness, functionality, etc.) have deemed them ideal platforms for removal of environmental contaminants, detoxification, and reduction of body burden from exogenous chemical exposures for prevention of disease initiation, and advanced treatment of chronic diseases, including cancer, diabetes, and cardiovascular disease. In this review, three main junctures where the use of hydrogel and hydrogel nanocomposite materials can intervene to positively impact human health are highlighted: 1) preventing exposures to environmental contaminants, 2) prophylactic treatments to prevent chronic disease initiation, and 3) treating chronic diseases after they have developed.
Laponite-Based Nanomaterials for Drug Delivery
Gita Kiaee, Nikolaos Dimitrakakis, Shabnam Sharifzadeh, Han-Jun Kim, Reginald K. Avery, Kamyar Mollozadeh Moghaddam, Reihaneh Haghniaz, Ezgi Pinar Yalcintas, Natan Roberto de Barros, Solmaz Karamikamkar, Alberto Libanori, Ali Khademhosseini, Parastoo Khoshakhlagh
doi : 10.1002/adhm.202102054
Laponite is a clay-based material composed of synthetic disk-shaped crystalline nanoparticles with highly ionic, large surface area. These characteristics enable the intercalation and dissolution of biomolecules in Laponite-based drug delivery systems. Furthermore, Laponite's innate physicochemical properties and architecture enable the development of tunable pH-responsive drug delivery systems. Laponite's coagulation capacity and cation exchangeability determine its exchange capabilities, drug encapsulation efficiency, and release profile. These parameters are exploited to design highly controlled and efficacious drug delivery platforms for sustained drug release. In this review, they provide an overview of how to design efficient delivery of therapeutics by leveraging the properties and specific interactions of various Laponite–polymer composites and drug moieties.
Engineered Tissue Models to Replicate Dynamic Interactions within the Hematopoietic Stem Cell Niche
Aidan E. Gilchrist, Brendan A. C. Harley
doi : 10.1002/adhm.202102130
Hematopoietic stem cells are the progenitors of the blood and immune system and represent the most widely used regenerative therapy. However, their rarity and limited donor base necessitate the design of ex vivo systems that support HSC expansion without the loss of long-term stem cell activity. This review describes recent advances in biomaterials systems to replicate features of the hematopoietic niche. Inspired by the native bone marrow, these instructive biomaterials provide stimuli and cues from cocultured niche-associated cells to support HSC encapsulation and expansion. Engineered systems increasingly enable study of the dynamic nature of the matrix and biomolecular environment as well as the role of cell–cell signaling (e.g., autocrine feedback vs paracrine signaling between dissimilar cells). The inherent coupling of material properties, biotransport of cell-secreted factors, and cell-mediated remodeling motivate dynamic biomaterial systems as well as characterization and modeling tools capable of evaluating a temporally evolving tissue microenvironment. Recent advances in HSC identification and tracking, model-based experimental design, and single-cell culture platforms facilitate the study of the effect of constellations of matrix, cell, and soluble factor signals on HSC fate. While inspired by the HSC niche, these tools are amenable to the broader stem cell engineering community.
Toward Gene Transfer Nanoparticles as Therapeutics
Erin W. Kavanagh, Jordan J. Green
doi : 10.1002/adhm.202102145
Genetic medicine has great potential to treat the underlying causes of many human diseases with exquisite precision, but the field has historically been stymied by delivery as the central challenge. Nanoparticles, engineered constructs the size of natural viruses, are being designed to more closely mimic the delivery efficiency of viruses, while enabling the advantages of increased safety, cargo-carrying flexibility, specific targeting, and ease in manufacturing. The speed in which nonviral gene transfer nanoparticles are making progress in the clinic is accelerating, with clinical validation of multiple nonviral nucleic acid delivery nanoparticle formulations recently FDA approved for both expression and for silencing of genes. While much of this progress has been with lipid nanoparticle formulations, significant development is being made with other nanomaterials for gene transfer as well, with favorable attributes such as biodegradability, scalability, and cell targeting. This review highlights the state of the field, current challenges in delivery, and opportunities for engineered nanomaterials to meet these challenges, including enabling long-term therapeutic gene editing. Delivery technology utilizing different kinds of nanomaterials and varying cargos for gene transfer (DNA, mRNA, and ribonucleoproteins) are discussed. Clinical applications are presented, including for the treatment of genetic diseases such as cystic fibrosis.
A 3D-Bioprinted Multiple Myeloma Model
Di Wu, Zongyi Wang, Jun Li, Yan Song, Manuel Everardo Mondragon Perez, Zixuan Wang, Xia Cao, Changliang Cao, Sushila Maharjan, Kenneth C. Anderson, Dharminder Chauhan, Yu Shrike Zhang
doi : 10.1002/adhm.202100884
Multiple myeloma (MM) is a malignancy of plasma cells accounting for ≈12% of hematological malignancies. In this study, the fabrication of a high-content in vitro MM model using a coaxial extrusion bioprinting method is reported, allowing formation of a human bone marrow-like microenvironment featuring an outer mineral-containing sheath and the inner soft hydrogel-based core. MM cells are mono-cultured or co-cultured with HS5 stromal cells that can release interleukin-6 (IL-6), where the cells show superior behaviors and responses to bortezomib in 3D models than in the planar cultures. Tocilizumab, a recombinant humanized anti-IL-6 receptor (IL-6R), is investigated for its efficacy to enhance the chemosensitivity of bortezomib on MM cells cultured in the 3D model by inhibiting IL-6R. More excitingly, in a proof-of-concept demonstration, it is revealed that patient-derived MM cells can be maintained in 3D-bioprinted microenvironment with decent viability for up to 7 days evaluated, whereas they completely die off in planar culture as soon as 5 days. In conclusion, a 3D-bioprinted MM model is fabricated to emulate some characteristics of the human bone marrow to promote growth and proliferation of the encapsulated MM cells, providing new insights for MM modeling, drug development, and personalized therapy in the future.
Injectable Acylhydrazone-Linked RAFT Polymer Hydrogels for Sustained Protein Release and Cell Encapsulation
Fang-Yi Lin, Nathan H. Dimmitt, Mariana Moraes de Lima Perini, Jiliang Li, Chien-Chi Lin
doi : 10.1002/adhm.202101284
A new class of temperature responsive polymer, termed PADO, is synthesized by reversible addition-fragmentation chain-transfer polymerization. Synthesized from copolymerization of diacetone acrylamide (DAAM), di(ethylene glycol) ethyl ether acrylate, and oligo(ethylene glycol) methyl ether acrylate, PADO polymer phase separates at temperature above its lower critical solution temperature (36–42 °C) due to enhanced hydrophobic interactions between the short ethylene glycol side chains. Solution of PADO polymers exhibit injectable shear-thinning properties and reach sol–gel transition rapidly (<5 min) at 37 °C. When the ketone moieties on DAAM are linked by adipic acid dihydrazdie, PADO polymers form crosslinked and injectable acylhydrazone hydrogels, which are hydrolytically degradable at a mild acidic environment owing to the pH sensitive acylhydrazone bonds. The pH-responsive degradation kinetics can be controlled by tuning polymer contents and ketone/hydrazide ratio. Importantly, the injectable PADO hydrogels are highly cytocompatible and can be easily formulated for pH-responsive sustained protein delivery.
Polysalicylic Acid Polymer Microparticle Decoys Therapeutically Treat Acute Respiratory Distress Syndrome
Emma R. Brannon, William J. Kelley, Michael W. Newstead, Alison L. Banka, Kathryn E. Uhrich, Colleen E. O'Connor, Theodore J. Standiford, Omolola Eniola-Adefeso
doi : 10.1002/adhm.202101534
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain problematic due to high mortality rates and lack of effective treatments. Neutrophilic injury contributes to mortality in ALI/ARDS. Here, technology for rapid ARDS intervention is developed and evaluated, where intravenous salicylic acid-based polymer microparticles, i.e., Poly-Aspirin (Poly-A), interfere with neutrophils in blood, reducing lung neutrophil infiltration and injury in vivo in mouse models of ALI/ARDS. Importantly, Poly-A particles reduce multiple inflammatory cytokines in the airway and bacterial load in the bloodstream in a live bacteria lung infection model of ARDS, drastically improving survival. It is observed that phagocytosis of the Poly-A microparticles, with salicylic acid in the polymer backbone, alters the neutrophil surface expression of adhesion molecules, potentially contributing to their added therapeutic benefits. Given the proven safety profile of the microparticle degradation products—salicylic acid and adipic acid—it is anticipated that the Poly-A particles represent a therapeutic strategy in ARDS with a rare opportunity for rapid clinical translation.
Template-Enabled Biofabrication of Thick 3D Tissues with Patterned Perfusable Macrochannels
Elham Davoodi, Hossein Montazerian, Masoud Zhianmanesh, Reza Abbasgholizadeh, Reihaneh Haghniaz, Avijit Baidya, Homeyra Pourmohammadali, Nasim Annabi, Paul S. Weiss, Ehsan Toyserkani, Ali Khademhosseini
doi : 10.1002/adhm.202102123
Interconnected pathways in 3D bioartificial organs are essential to retaining cell activity in thick functional 3D tissues. 3D bioprinting methods have been widely explored in biofabrication of functionally patterned tissues; however, these methods are costly and confined to thin tissue layers due to poor control of low-viscosity bioinks. Here, cell-laden hydrogels that could be precisely patterned via water-soluble gelatin templates are constructed by economical extrusion 3D printed plastic templates. Tortuous co-continuous plastic networks, designed based on triply periodic minimal surfaces (TPMS), serve as a sacrificial pattern to shape the secondary sacrificial gelatin templates. These templates are eventually used to form cell-encapsulated gelatin methacryloyl (GelMA) hydrogel scaffolds patterned with the complex interconnected pathways. The proposed fabrication process is compatible with photo-crosslinkable hydrogels wherein prepolymer casting enables incorporation of high cell populations with high viability. The cell-laden hydrogel constructs are characterized by robust mechanical behavior. In vivo studies demonstrate a superior cell ingrowth into the highly permeable constructs compared to the bulk hydrogels. Perfusable complex interconnected networks within cell-encapsulated hydrogels may assist in engineering thick and functional tissue constructs through the permeable internal channels for efficient cellular activities in vivo.
Effects of Hydrophobicity on Antimicrobial Activity, Selectivity, and Functional Mechanism of Guanidinium-Functionalized Polymers
Jason Tan, Yanli Zhao, James L. Hedrick, Yi Yan Yang
doi : 10.1002/adhm.202100482
In this study, a series of guanidinium-functionalized polycarbonate random co-polymers is prepared from organocatalytic ring-opening polymerization to investigate the effect of the hydrophobic side chain (ethyl, propyl, isopropyl, benzyl, and hexyl) on their antimicrobial activity and selectivity. Although the polymers exhibit similar minimum inhibitory concentrations, the more hydrophobic polymers exhibit a faster rate of bacteria elimination. At higher percentage content (20 mol%), polymers with more hydrophobic side chains suffer from poor selectivity due to their high hemolytic activity. The highly hydrophobic co-polymer, containing the hydrophobic hexyl-functionalized cyclic carbonate, kills bacteria via a membrane-disruptive mechanism. Micelle formation leads to a lower extent of membrane disruption. This study unravels the effects of hydrophobic side chains on the activities of the polymers and their killing mechanism, providing insights into the design of new antimicrobial polymers.
One Week Sustained In Vivo Therapeutic Release and Safety of Novel Extended-Wear Silicone Hydrogel Contact Lenses
Stephen A. DiPasquale, Liana D. Wuchte, Robert J. Mosley, Renee M. Demarest, Meredith L. Voyles, Mark E. Byrne
doi : 10.1002/adhm.202101263
Since the seminal work of Wichterle in 1965 describing the first soft contact lenses and their potential for ocular drug delivery, the field has yet to realize his vision. Maintaining all lens commercial properties combined with a mechanism for controlled drug release of therapeutically relevant concentrations for duration of wear is a major challenge. Here, successful in vivo week-long sustained release of a small molecular weight therapeutic in rabbits from extended-wear silicone hydrogel contact lenses meeting all commercial specifications by utilizing a novel macromolecular memory strategy is reported for the first time. Lens-treated eyes show a continuous, therapeutically relevant bromfenac tear concentration of 256.4 ± 23.1 µg mL−1 for 8 days. Bromday (bromfenac ophthalmic solution, 0.09%, Bausch+Lomb) topical drops exhibit a quick peak concentration of 269.3 ± 85.7 µg mL−1 and 100 min duration. Bioavailability (AUC0-8days) and mean residence time of lenses are 26 and 155 times higher than drops, respectively. Lenses are safe, well tolerated, and no corneal histological differences are observed. This work highlights the enormous potential of drug releasing lenses as a platform strategy, and offers a new dropless clinical strategy for post-cataract, uveitis, post-LASIK, and corneal abrasion treatment.
A Spheroid Model of Early and Late-Stage Osteosarcoma Mimicking the Divergent Relationship between Tumor Elimination and Bone Regeneration
Fiona E. Freeman, Ross Burdis, Olwyn R. Mahon, Daniel J. Kelly, Natalie Artzi
doi : 10.1002/adhm.202101296
Osteosarcoma is the most diagnosed bone tumor in children. The use of tissue engineering strategies after malignant tumor resection remains a subject of scientific controversy. As a result, there is limited research that focuses on bone regeneration postresection, which is further compromised following chemotherapy. This study aims to develop the first co-culture spheroid model for osteosarcoma, to understand the divergent relationship between tumor elimination and bone regeneration. By manipulating the ratio of stromal to osteosarcoma cells the modelled cancer state (early/late) is modified, as is evident by the increased tumor growth rates and an upregulation of a panel of well-established osteosarcoma prognostic genes. Validation of the authors' model is conducted by analyzing its ability to mimic the cytotoxic effects of the FDA-approved chemotherapeutic Doxorubicin. Next, the model is used to investigate what effect osteogenic supplements have, if any, on tumor growth. When their model is treated with osteogenic supplements, there is a stimulatory effect on the surrounding stromal cells. However, when treated with chemotherapeutics this stimulatory effect is significantly diminished. Together, the results of this study present a novel multicellular model of osteosarcoma and provide a unique platform for screening potential therapeutic options for osteosarcoma before conducting in vivo experiments.
Biopolymer Nano-Network for Antimicrobial Peptide Protection and Local Delivery
Natthaporn Klubthawee, Giovanni Bovone, Bruno Marco-Dufort, Elia A. Guzzi, Ratchaneewan Aunpad, Mark W. Tibbitt
doi : 10.1002/adhm.202101426
Antimicrobial resistance (AMR) develops when bacteria no longer respond to conventional antimicrobial treatment. The limited treatment options for resistant infections result in a significantly increased medical burden. Antimicrobial peptides offer advantages for treatment of resistant infections, including broad-spectrum activity and lower risk of resistance development. However, sensitivity to proteolytic cleavage often limits their clinical application. Here, a moldable and biodegradable colloidal nano-network is presented that protects bioactive peptides from enzymatic degradation and delivers them locally. An antimicrobial peptide, PA-13, is encapsulated electrostatically into positively and negatively charged nanoparticles made of chitosan and dextran sulfate without requiring chemical modification. Mixing and concentration of oppositely charged particles form a nano-network with the rheological properties of a cream or injectable hydrogel. After exposure to proteolytic enzymes, the formed nano-network loaded with PA-13 eliminates Pseudomonas aeruginosa during in vitro culture and in an ex vivo porcine skin model while the unencapsulated PA-13 shows no antibacterial effect. This demonstrates the ability of the nano-network to protect the antimicrobial peptide in an enzyme-challenged environment, such as a wound bed. Overall, the nano-network presents a useful platform for antimicrobial peptide protection and delivery without impacting peptide bioactivity.
Initial Formation of the Skin Layer of PLGA Microparticles
Farrokh Sharifi, Andrew Otte, Kinam Park
doi : 10.1002/adhm.202101427
Poly(lactide-co-glycolide) (PLGA) has been extensively used in making long-acting injectable formulations. The critical factors affecting the PLGA formulation properties have been adjusted to control the drug release kinetics and obtain desirable properties of PLGA-based drug delivery systems. The PLGA microparticle formation begins as soon as the drug/PLGA-dissolved in the organic solvent phase (oil phase) is exposed to the water phase. The initial skin (or shell) formation on the oil droplets occurs very quickly, sometimes in the matter of milliseconds, and studying the process has been difficult. The skin formation on the PLGA emulsion droplet surface that can affect the subsequent hardening steps is examined. PLGA droplets with different compositions are prepared. Using collimated light and a high-speed camera made it possible to detect the diffusion of acetonitrile from the oil phase into the water phase during the oil droplet formation. Although the skin formation is not visible on the surface of the oil phase droplet with the current setup, the droplet shapes, solid strand formation, and the difference in the spreading time suggest that the initial contact time between the oil and water phases in the range of a few seconds is critical to the properties of the skin.
In Vivo Antitumor and Antimetastatic Efficacy of a Polyacetal-Based Paclitaxel Conjugate for Prostate Cancer Therapy
Yolanda Fernández, Julie Movellan, Laia Foradada, Vanessa Giménez, Natalia GarcÃa-Aranda, Sandra Mancilla, Ana Armiñán, Sven Even Borgos, Astrid Hyldbakk, Anna Bogdanska, Oliviero L. Gobbo, Adriele Prina-Mello, Jessica Ponti, Luigi Calzolai, Oleksandr Zagorodko, Elena Gallon, Amaya Niño-Pariente, Alison Paul, Simó Schwartz Jr, Ibane Abasolo, MarÃa J. Vicent
doi : 10.1002/adhm.202101544
Prostate cancer (PCa), one of the leading causes of cancer-related deaths, currently lacks effective treatment for advanced-stage disease. Paclitaxel (PTX) is a highly active chemotherapeutic drug and the first-line treatment for PCa; however, conventional PTX formulation causes severe hypersensitivity reactions and limits PTX use at high concentrations. In the pursuit of high molecular weight, biodegradable, and pH-responsive polymeric carriers, one conjugates PTX to a polyacetal-based nanocarrier to yield a tert-Ser-PTX polyacetal conjugate. tert-Ser-PTX conjugate provides sustained release of PTX over 2 weeks in a pH-responsive manner while also obtaining a degree of epimerization of PTX to 7-epi-PTX. Serum proteins stabilize tert-Ser-PTX, with enhanced stability in human serum versus PBS (pH 7.4). In vitro efficacy assessments in PCa cells demonstrate IC50 values above those for the free form of PTX due to the differential cell trafficking modes; however, in vivo tolerability assays demonstrate that tert-Ser-PTX significantly reduces the systemic toxicities associated with free PTX treatment. tert-Ser-PTX also effectively inhibits primary tumor growth and hematologic, lymphatic, and coelomic dissemination, as confirmed by in vivo and ex vivo bioluminescence imaging and histopathological evaluations in mice carrying orthotopic LNCaP tumors. Overall, the results suggest the application of tert-Ser-PTX as a robust antitumor/antimetastatic treatment for PCa.
Impact of Collagen Triple Helix Structure on Melanoma Cell Invadopodia Formation and Matrix Degradation upon BRAF Inhibitor Treatment
Della S. Shin, Megan E. Schroeder, Kristi S. Anseth
doi : 10.1002/adhm.202101592
A collagen-rich tumor microenvironment (TME) is associated with worse outcomes in cancer patients and contributes to drug resistance in many cancer types. In melanoma, stiff and fibrillar collagen-abundant tissue is observed after failure of therapeutic treatments with BRAF inhibitors. Increased collagen in the TME can affect properties of the extracellular matrix (ECM), including stiffness, adhesiveness, and interaction of integrins with triple helix forming nanostructures. Decoupling these biochemical and biophysical properties of the ECM can lead to a better understanding of how each of these individual properties affect melanoma cancer behavior and drug efficacy. In addition, as drug treatment can induce cancer cell phenotypic switch, cancer cell responsiveness to the TME can be dynamically changed during therapeutic treatments. To investigate cancer cell phenotype changes and the role of the cancer TME, poly(ethylene glycol) (PEG) hydrogels functionalized with collagen mimetic peptides (CMPs) is utilized, or an interpenetrating network (IPN) of type І collagen within the PEG system to culture various melanoma cell lines in the presence or absence of Vemurafenib (PLX4032) drug treatment is prepared. Additionally, the potential of using CMP functionalized PEG hydrogels, which can provide better tunability is explored, to replace the existing invadopodia assay platform based on fluorescent gelatin.
Computational Modeling and Experimental Characterization of Extrusion Printing into Suspension Baths
Margaret E. Prendergast, Jason A. Burdick
doi : 10.1002/adhm.202101679
The extrusion printing of inks into suspension baths is an exciting tool, as it allows the printing of diverse and soft hydrogel inks into 3D space without the need for layer-by-layer fabrication. However, this printing process is complex and there have been limited studies to experimentally and computationally characterize the process. In this work, hydrogel inks (i.e., gelatin methacrylamide (GelMA)), suspension baths (i.e., agarose, Carbopol), and the printing process are examined via rheological, computational, and experimental analyses. Rheological data on various hydrogel inks and suspension baths is utilized to develop computational printing simulations based on Carreau constitutive viscosity models of the printing of inks within suspension baths. These results are then compared to experimental outcomes using custom print designs where features such as needle translation speed, defined in this work as print speed, are varied and printed filament resolution is quantified. Results are then used to identify print parameters for the printing of a GelMA ink into a unique guest–host hyaluronic acid suspension bath. This work emphasizes the importance of key rheological properties and print parameters for suspension bath printing and provides a computational model and experimental tools that can be used to inform the selection of print settings.
Rational Design of Hydrogel Networks with Dynamic Mechanical Properties to Mimic Matrix Remodeling
Katherine L. Wiley, Bryan P. Sutherland, Babatunde A. Ogunnaike, April M. Kloxin
doi : 10.1002/adhm.202101947
Engineered hydrogels are increasingly used as extracellular matrix (ECM) surrogates for probing cell function in response to ECM remodeling events related to injury or disease (e.g., degradation followed by deposition/crosslinking). Inspired by these events, this work establishes an approach for pseudo-reversible mechanical property modulation in synthetic hydrogels by integrating orthogonal, enzymatically triggered crosslink degradation, and light-triggered photopolymerization stiffening. Hydrogels are formed by a photo-initiated thiol–ene reaction between multiarm polyethylene glycol and a dually enzymatically degradable peptide linker, which incorporates a thrombin-degradable sequence for triggered softening and a matrix metalloproteinase (MMP)-degradable sequence for cell-driven remodeling. Hydrogels are stiffened by photopolymerization using a flexible, MMP-degradable polymer-peptide conjugate and multiarm macromers, increasing the synthetic matrix crosslink density while retaining degradability. Integration of these tools enables sequential softening and stiffening inspired by matrix remodeling events within loose connective tissues (Young's modulus (E) ≈5 to 1.5 to 6 kPa with >3x ΔE). The cytocompatibility and utility of this approach is examined with breast cancer cells, where cell proliferation shows a dependence on the timing of triggered softening. This work provides innovative tools for 3D dynamic property modulation that are synthetically accessible and cell compatible.
Encapsulation of Primary Salivary Gland Acinar Cell Clusters and Intercalated Ducts (AIDUCs) within Matrix Metalloproteinase (MMP)-Degradable Hydrogels to Maintain Tissue Structure and Function
Yuanhui Song, Azmeer Sharipol, Hitoshi Uchida, Matthew H. Ingalls, Lindsay Piraino, Jared A. Mereness, Tracey Moyston, Lisa A. DeLouise, Catherine E. Ovitt, Danielle S. W. Benoit
doi : 10.1002/adhm.202101948
Progress in the development of salivary gland regenerative strategies is limited by poor maintenance of the secretory function of salivary gland cells (SGCs) in vitro. To reduce the precipitous loss of secretory function, a modified approach to isolate intact acinar cell clusters and intercalated ducts (AIDUCs), rather than commonly used single cell suspension, is investigated. This isolation approach yields AIDUCs that maintain many of the cell–cell and cell-matrix interactions of intact glands. Encapsulation of AIDUCs in matrix metalloproteinase (MMP)-degradable PEG hydrogels promotes self-assembly into salivary gland mimetics (SGm) with acinar-like structure. Expression of Mist1, a transcription factor associated with secretory function, is detectable throughout the in vitro culture period up to 14 days. Immunohistochemistry also confirms expression of acinar cell markers (NKCC1, PIP and AQP5), duct cell markers (K7 and K5), and myoepithelial cell markers (SMA). Robust carbachol and ATP-stimulated calcium flux is observed within the SGm for up to 14 days after encapsulation, indicating that secretory function is maintained. Though some acinar-to-ductal metaplasia is observed within SGm, it is reduced compared to previous reports. In conclusion, cell–cell interactions maintained within AIDUCs together with the hydrogel microenvironment may be a promising platform for salivary gland regenerative strategies.
