Publications by authors named "Mark W Tibbitt"

57 Publications

Controlled delivery of gold nanoparticle-coupled miRNA therapeutics an injectable self-healing hydrogel.

Nanoscale 2021 Nov 24. Epub 2021 Nov 24.

David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge 02142, MA, USA.

Differential expression of microRNAs (miRNAs) plays a role in many diseases, including cancer and cardiovascular diseases. Potentially, miRNAs could be targeted with miRNA-therapeutics. Sustained delivery of these therapeutics remains challenging. This study couples miR-mimics to PEG-peptide gold nanoparticles (AuNP) and loads these AuNP-miRNAs in an injectable, shear thinning, self-assembling polymer nanoparticle (PNP) hydrogel drug delivery platform to improve delivery. Spherical AuNPs coated with fluorescently labelled miR-214 are loaded into an HPMC-PEG-b-PLA PNP hydrogel. Release of AuNP/miRNAs is quantified, AuNP-miR-214 functionality is shown in HEK293 cells, and AuNP-miRNAs are tracked in a 3D bioprinted human model of calcific aortic valve disease (CAVD). Lastly, biodistribution of PNP-AuNP-miR-67 is assessed after subcutaneous injection in C57BL/6 mice. AuNP-miRNA release from the PNP hydrogel demonstrates a linear pattern over 5 days up to 20%. AuNP-miR-214 transfection in HEK293 results in 33% decrease of Luciferase reporter activity. In the CAVD model, AuNP-miR-214 are tracked into the cytoplasm of human aortic valve interstitial cells. Lastly, 11 days after subcutaneous injection, AuNP-miR-67 predominantly clears the liver and kidneys, and fluorescence levels are again comparable to control animals. Thus, the PNP-AuNP-miRNA drug delivery platform provides linear release of functional miRNAs and has potential for applications.
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http://dx.doi.org/10.1039/d1nr04973aDOI Listing
November 2021

Additive manufacturing in drug delivery: Innovative drug product design and opportunities for industrial application.

Adv Drug Deliv Rev 2021 11 30;178:113990. Epub 2021 Sep 30.

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142, United States; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142, United States. Electronic address:

Additive manufacturing (AM) or 3D printing is enabling new directions in product design. The adoption of AM in various industrial sectors has led to major transformations. Similarly, AM presents new opportunities in the field of drug delivery, opening new avenues for improved patient care. In this review, we discuss AM as an innovative tool for drug product design. We provide a brief overview of the different AM processes and their respective impact on the design of drug delivery systems. We highlight several enabling features of AM, including unconventional release, customization, and miniaturization, and discuss several applications of AM for the fabrication of drug products. This includes products that have been approved or are in development. As the field matures, there are also several new challenges to broad implementation in the pharmaceutical landscape. We discuss several of these from the regulatory and industrial perspectives and provide an outlook for how these issues may be addressed. The introduction of AM into the field of drug delivery is an enabling technology and many new drug products can be created through productive collaboration of engineers, materials scientists, pharmaceutical scientists, and industrial partners.
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http://dx.doi.org/10.1016/j.addr.2021.113990DOI Listing
November 2021

Hierarchical biomaterials via photopatterning-enhanced direct ink writing.

Biofabrication 2021 09 9;13(4). Epub 2021 Sep 9.

Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering, ETH Zurich, Sonneggstrasse 3, Zurich 8092, Switzerland.

Recent advances in additive manufacturing (AM) technologies provide tools to fabricate biological structures with complex three-dimensional (3D) organization. Deposition-based approaches have been exploited to manufacture multimaterial constructs. Stimulus-triggered approaches have been used to fabricate scaffolds with high resolution. Both features are useful to produce biomaterials that mimic the hierarchical organization of human tissues. Recently, multitechnology biofabrication approaches have been introduced that integrate benefits from different AM techniques to enable more complex materials design. However, few methods allow for tunable properties at both micro- and macro-scale in materials that are conducive for cell growth. To improve the organization of biofabricated constructs, we integrated direct ink writing (DIW) with digital light processing (DLP) to form multimaterial constructs with improved spatial control over final scaffold mechanics. Polymer-nanoparticle hydrogels were combined with methacryloyl gelatin (GelMA) to engineer dual inks that were compatible with both DIW and DLP. The shear-thinning and self-healing properties of the dual inks enabled extrusion-based 3D printing. The inclusion of GelMA provided a handle for spatiotemporal control of cross-linking with DLP. Exploiting this technique, complex multimaterial constructs were printed with defined mechanical reinforcement. In addition, the multitechnology approach was used to print live cells for biofabrication applications. Overall, the combination of DIW and DLP is a simple and efficient strategy to fabricate hierarchical biomaterials with user-defined control over material properties at both micro- and macro-scale.
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http://dx.doi.org/10.1088/1758-5090/ac212fDOI Listing
September 2021

Long-term Normothermic Machine Preservation of Partial Livers: First Experience With 21 Human Hemi-livers.

Ann Surg 2021 11;274(5):836-842

Wyss Zurich, ETH Zurich/University of Zurich, Switzerland.

Objective: The aim of this study was to maintain long-term full function and viability of partial livers perfused ex situ for sufficient duration to enable ex situ treatment, repair, and regeneration.

Background: Organ shortage remains the single most important factor limiting the success of transplantation. Autotransplantation in patients with nonresectable liver tumors is rarely feasible due to insufficient tumor-free remnant tissue. This limitation could be solved by the availability of long-term preservation of partial livers that enables functional regeneration and subsequent transplantation.

Methods: Partial swine livers were perfused with autologous blood after being procured from healthy pigs following 70% in-vivo resection, leaving only the right lateral lobe. Partial human livers were recovered from patients undergoing anatomic right or left hepatectomies and perfused with a blood based perfusate together with various medical additives. Assessment of physiologic function during perfusion was based on markers of hepatocyte, cholangiocyte, vascular and immune compartments, as well as histology.

Results: Following the development phase with partial swine livers, 21 partial human livers (14 right and 7 left hemi-livers) were perfused, eventually reaching the targeted perfusion duration of 1 week with the final protocol. These partial livers disclosed a stable perfusion with normal hepatic function including bile production (5-10 mL/h), lactate clearance, and maintenance of energy exhibited by normal of adenosine triphosphate (ATP) and glycogen levels, and preserved liver architecture for up to 1 week.

Conclusion: This pioneering research presents the inaugural evidence for long-term machine perfusion of partial livers and provides a pathway for innovative and relevant clinical applications to increase the availability of organs and provide novel approaches in hepatic oncology.
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http://dx.doi.org/10.1097/SLA.0000000000005102DOI Listing
November 2021

Synthesis of coagulation factors during long-term ex situ liver perfusion.

Artif Organs 2021 Jul 20. Epub 2021 Jul 20.

Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.

Robust viability assessment of grafts during normothermic liver perfusion is a prerequisite for organ use. Coagulation parameters are used commonly for liver assessment in patients. However, they are not yet included in viability assessment during ex situ perfusion. In this study, we analysed coagulation parameters during one week ex situ perfusion at 34℃. Eight discarded human livers were perfused with blood-based, heparinised perfusate for one week; perfusions in a further four livers were terminated on day 4 due to massive ongoing cell death. Coagulation parameters were well below the physiologic range at perfusion start. Physiologic levels were achieved within the first two perfusion days for factor V (68.5 ± 35.5%), factor VII (83.5 ± 26.2%), fibrinogen (2.1 ± 0.4 g/L) and antithrombin (107 ± 26.5%) in the livers perfused for one week. Despite the increased production of coagulation factors, INR was detectable only at 24h of perfusion (2.1 ± 0.3) and prolonged thereafter (INR > 9). The prolongation of INR was related to the high heparin level in the perfusate (anti-FXa > 3 U/mL). Intriguingly, livers with ongoing massive cell death also disclosed synthesis of factor V and improved INR. In summary, perfused livers were able to produce coagulation factors at a physiological level ex situ. We propose that single coagulation factor analysis is more reliable for assessing the synthetic function of perfused livers as compared to INR when using a heparinised perfusate.
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http://dx.doi.org/10.1111/aor.14041DOI Listing
July 2021

Sources and prevention of graft infection during long-term ex situ liver perfusion.

Transpl Infect Dis 2021 Aug 22;23(4):e13623. Epub 2021 Jun 22.

Department of Surgery, Swiss Hepatopancreatobiliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.

Introduction: The use of normothermic liver machine perfusion to repair injured grafts ex situ is an emerging topic of clinical importance. However, a major concern is the possibility of microbial contamination in the absence of a fully functional immune system. Here, we report a standardized approach to maintain sterility during normothermic liver machine perfusion of porcine livers for one week.

Methods: Porcine livers (n = 42) were procured and perfused with blood at 34°C following aseptic technique and standard operating procedures. The antimicrobial prophylaxis was adapted and improved in a step-wise manner taking into account the pathogens that were detected during the development phase. Piperacillin-Tazobactam was applied as a single dose initially and modified to continuous application in the final protocol. In addition, the perfusion machine was improved to recapitulate partially the host's defense system. The final protocol was tested for infection prevention during one week of perfusion.

Results: During the development phase, microbial contamination occurred in 27 out of 39 (69%) livers with a mean occurrence of growth on 4 ± 1.6 perfusion days. The recovered microorganisms suggested an exogenous source of microbial contamination. The antimicrobial agents (piperacillin/tazobactam) could be maintained above the targeted minimal inhibitory concentration (8-16 mg/L) only with continuous application. In addition to continuous application of piperacillin/tazobactam, partial recapitulation of the host immune system ex situ accompanied by strict preventive measures for contact and air contamination maintained sterility during one week of perfusion.

Conclusion: The work demonstrates feasibility of sterility maintenance for one week during ex situ normothermic liver perfusion.
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http://dx.doi.org/10.1111/tid.13623DOI Listing
August 2021

Engineering Hydrogel Adhesion for Biomedical Applications via Chemical Design of the Junction.

ACS Biomater Sci Eng 2021 09 1;7(9):4048-4076. Epub 2021 Apr 1.

Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering, ETH Zurich, 8092 Zurich, Switzerland.

Hydrogel adhesion inherently relies on engineering the contact surface at soft and hydrated interfaces. Upon contact, adhesion normally occurs through the formation of chemical or physical interactions between the disparate surfaces. The ability to form these adhesion junctions is challenging for hydrogels as the interfaces are wet and deformable and often contain low densities of functional groups. In this Review, we link the design of the binding chemistries or adhesion junctions, whether covalent, dynamic covalent, supramolecular, or physical, to the emergent adhesive properties of soft and hydrated interfaces. Wet adhesion is useful for bonding to or between tissues and implants for a range of biomedical applications. We highlight several recent and emerging adhesive hydrogels for use in biomedicine in the context of efficient junction design. The main focus is on engineering hydrogel adhesion through molecular design of the junctions to tailor the adhesion strength, reversibility, stability, and response to environmental stimuli.
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http://dx.doi.org/10.1021/acsbiomaterials.0c01677DOI Listing
September 2021

Supramolecular engineering of hydrogels for drug delivery.

Adv Drug Deliv Rev 2021 04 7;171:240-256. Epub 2021 Feb 7.

Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering, ETH Zurich, 8092 Zurich, Switzerland. Electronic address:

Supramolecular binding motifs are increasingly employed in the design of biomaterials. The ability to rationally engineer specific yet reversible associations into polymer networks with supramolecular chemistry enables injectable or sprayable hydrogels that can be applied via minimally invasive administration. In this review, we highlight two main areas where supramolecular binding motifs are being used in the design of drug delivery systems: engineering network mechanics and tailoring drug-material affinity. Throughout, we highlight many of the established and emerging chemistries or binding motifs that are useful for the design of supramolecular hydrogels for drug delivery applications.
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http://dx.doi.org/10.1016/j.addr.2021.02.002DOI Listing
April 2021

Bile formation in long-term ex situ perfused livers.

Surgery 2021 04 6;169(4):894-902. Epub 2021 Jan 6.

Department of Surgery, Swiss Hepatopancreatobiliary and Transplantation Center, University Hospital Zurich, Switzerland. Electronic address:

Background: Long-term ex situ liver perfusion may rescue injured grafts. Little is known about bile flow during long-term perfusion. We report the development of a bile stimulation protocol and motivate bile flow as a viability marker during long-term ex situ liver perfusion.

Methods: Porcine and human livers were perfused with blood at close to physiologic conditions. Our perfusion protocol was established during phase 1 with porcine livers (n = 23). Taurocholic acid was applied to stimulate bile flow. The addition of piperacillin-tazobactam (tazobac) and methylprednisolone was modified from daily bolus to controlled continuous application. We adapted the protocol to human livers (n = 12) during phase 2. Taurocholic acid was replaced with medical grade ursodeoxycholic acid.

Results: Phase 2: Despite administering taurocholic acid, bile flow declined from 29.3 ± 6.5 to 9.3 ± 1.4 mL/h (P < .001). Shortly after bolus of tazobac/methylprednisolone, bile flow recovered to 39.0 ± 9.7 mL/h with a decrease of solid bile components. This implied bile salt independent bile flow stimulation by tazobac/methylprednisolone. Phase 2: Ursodeoxycholic acid was shown to stimulate bile flow ex situ in human livers. Eight livers were perfused successfully for 1 week with continuous bile flow. The other 4 livers demonstrated progressive cell death, of which only 1 exhibited bile flow.

Conclusion: A lack of bile flow stimulation leads to a decline in bile flow and is not necessarily a sign of deterioration in liver function. Proper administration of stimulators can induce constant bile flow during ex situ liver perfusion for up to 1 week. Medical grade ursodeoxycholic acid is a suitable replacement for nonmedical grade taurocholic acid. The presence of bile flow alone is not sufficient to assess liver viability.
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http://dx.doi.org/10.1016/j.surg.2020.11.042DOI Listing
April 2021

Hyperoxia in portal vein causes enhanced vasoconstriction in arterial vascular bed.

Sci Rep 2020 12 1;10(1):20966. Epub 2020 Dec 1.

Department of Surgery, Swiss Hepato-Pancreato-Biliary and Transplantation Center, University Hospital Zurich, Zurich, Switzerland.

Long-term perfusion of liver grafts outside of the body may enable repair of poor-quality livers that are currently declined for transplantation, mitigating the global shortage of donor livers. In current ex vivo liver perfusion protocols, hyperoxic blood (arterial blood) is commonly delivered in the portal vein (PV). We perfused porcine livers for one week and investigated the effect of and mechanisms behind hyperoxia in the PV on hepatic arterial resistance. Applying PV hyperoxia in porcine livers (n = 5, arterial PV group), we observed an increased need for vasodilator Nitroprussiat (285 ± 162 ml/week) to maintain the reference hepatic artery flow of 0.25 l/min during ex vivo perfusion. With physiologic oxygenation (venous blood) in the PV the need for vasodilator could be reduced to 41 ± 34 ml/week (p = 0.011; n = 5, venous PV group). This phenomenon has not been reported previously, owing to the fact that such experiments are not feasible practically in vivo. We investigated the mechanism of the variation in HA resistance in response to blood oxygen saturation with a focus on the release of vasoactive substances, such as Endothelin 1 (ET-1) and nitric oxide (NO), at the protein and mRNA levels. However, no difference was found between groups for ET-1 and NO release. We propose direct oxygen sensing of endothelial cells and/or increased NO break down rate with hyperoxia as possible explanations for enhanced HA resistance.
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http://dx.doi.org/10.1038/s41598-020-77915-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708838PMC
December 2020

Automated Insulin Delivery - Continuous Blood Glucose Control During Ex Situ Liver Perfusion.

IEEE Trans Biomed Eng 2021 04 18;68(4):1399-1408. Epub 2021 Mar 18.

Objective: With the growing demand for livers in the field of transplantation, interest in normothermic ex situ machine perfusion (NMP) has increased in recent years. This may open the door for novel therapeutic interventions such as repair of suboptimal grafts. For successful long-term NMP of livers, blood glucose (BG) levels need to be maintained in a close to physiological range.

Methods: We present an "automated insulin delivery" (AID) system integrated into an NMP system, which automatically adjusts insulin infusion rates based on continuous BG measurements in a closed loop manner during ex situ pig and human liver perfusion. An online glucose sensor for continuous glucose monitoring was integrated and evaluated in blood. A model based and a proportional controller were implemented and compared in their ability to maintain BG within the physiological range.

Results: The continuous glucose sensor is capable of measuring BG directly in human and pig blood for multiple days with an average error of 0.6 mmol/L. There was no significant difference in the performance of the two controllers in terms of their ability to keep BG in the physiological range. With the integrated AID, BG was controlled within the physiological range on average in 80% and 76% of the perfusion time for human and pig livers, respectively.

Conclusion: The presented work offers a method and shows the feasibility to maintain BG in the physiological range for multiple (up to ten) days during ex situ liver perfusion with the help of an automated AID.

Significance: Maintaining BG within the physiological range is required to enable long-term ex situ liver perfusion.
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http://dx.doi.org/10.1109/TBME.2020.3033663DOI Listing
April 2021

Screening method to identify hydrogel formulations that facilitate myotube formation from encapsulated primary myoblasts.

Bioeng Transl Med 2020 Sep 3;5(3):e10181. Epub 2020 Sep 3.

Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering ETH Zurich Zurich Switzerland.

Hydrogel-based three-dimensional (3D) cellular models are attractive for bioengineering and pharmaceutical development as they can more closely resemble the cellular function of native tissue outside of the body. In general, these models are composed of tissue specific cells embedded within a support material, such as a hydrogel. As hydrogel properties directly affect cell function, hydrogel composition is often tailored to the cell type(s) of interest and the functional objective of the model. Here, we develop a parametric analysis and screening method to identify suitable encapsulation conditions for the formation of myotubes from primary murine myoblasts in methacryloyl gelatin (GelMA) hydrogels. The effect of the matrix properties on the myotube formation was investigated by varying GelMA weight percent (wt%, which controls gel modulus), cell density, and Matrigel concentration. Contractile myotubes form via myoblast fusion and are characterized by myosin heavy chain (MyHC) expression. To efficiently screen the gel formulations, we developed a fluorescence-based plate reader assay to quantify MyHC staining in the gel samples, as a metric of myotube formation. We observed that lower GelMA wt% resulted in increased MyHC staining (myotube formation). The cell density did not significantly affect MyHC staining, while the inclusion of Matrigel increased MyHC staining, however, a concentration dependent effect was not observed. These findings were supported by the observation of spontaneously contracting myotubes in samples selected in the initial screen. This work provides a method to rapidly screen hydrogel formulations for the development of 3D cellular models and provides specific guidance on the formulation of gels for myotube formation from primary murine myoblasts in 3D.
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http://dx.doi.org/10.1002/btm2.10181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510461PMC
September 2020

Human Retinal Microvasculature-on-a-Chip for Drug Discovery.

Adv Healthc Mater 2020 11 24;9(21):e2001531. Epub 2020 Sep 24.

Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, 4070, Switzerland.

Retinal cells within neurovascular units generate the blood-retinal barrier (BRB) to regulate the local retinal microenvironment and to limit access to inflammatory cells. Breakdown of the endothelial junctional complexes in the BRB negatively affects neuronal signaling and ultimately causes vision loss. As new therapeutics are being developed either to prevent barrier disruption or to restore barrier function, access to physiologically relevant human in vitro tissue models that recapitulate important features of barrier biology is essential for disease modeling, target validation, and toxicity assessment. Here, a tunable organ-on-a-chip model of the retinal microvasculature using human retinal microvascular endothelial cells with integrated flow is described. Automated imaging and image analysis methods are employed for facile screening of leakage mediators and cytokine inhibitors on barrier properties. The developed retinal microvasculature-on-a-chip will enable improved understanding of BRB biology and provide an additional tool for drug discovery.
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http://dx.doi.org/10.1002/adhm.202001531DOI Listing
November 2020

Bioprinting within live animals.

Authors:
Mark W Tibbitt

Nat Biomed Eng 2020 09;4(9):851-852

Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering, ETH Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1038/s41551-020-00609-5DOI Listing
September 2020

Surface Tension-Assisted Additive Manufacturing of Tubular, Multicomponent Biomaterials.

Methods Mol Biol 2021 ;2147:149-160

Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering, ETH Zürich, Zürich, Switzerland.

The fabrication of functional biomaterials for organ replacement and tissue repair remains a major goal of biomedical engineering. Advances in additive manufacturing (AM) technologies and computer-aided design (CAD) are advancing the tools available for the production of these devices. Ideally, these constructs should be matched to the geometry and mechanical properties of the tissue at the needed implant site. To generate geometrically defined and structurally supported multicomponent and cell-laden biomaterials, we have developed a method to integrate hydrogels with 3D-printed lattice scaffolds leveraging surface tension-assisted AM.
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http://dx.doi.org/10.1007/978-1-0716-0611-7_13DOI Listing
March 2021

Environment Controls Biomolecule Release from Dynamic Covalent Hydrogels.

Biomacromolecules 2021 01 11;22(1):146-157. Epub 2020 Sep 11.

Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering, ETH Zurich, 8092 Zurich, Switzerland.

Moldable hydrogels composed of dynamic covalent bonds are attractive biomaterials for controlled release, as the dynamic exchange of bonds in these networks enables minimally invasive application via injection. Despite the growing interest in the biomedical application of dynamic covalent hydrogels, there is a lack of fundamental understanding as to how the network design and local environment control the release of biomolecules from these materials. In this work, we fabricated boronic-ester-based dynamic covalent hydrogels for the encapsulation and in vitro release of a model biologic (β-galactosidase). We systematically investigated the role of network properties and of the external environment (temperature and presence of competitive binders) on release from these dynamic covalent hydrogels. We observed that surface erosion (and associated mass loss) governed biomolecule release. In addition, we developed a statistical model of surface erosion based on the binding equilibria in a boundary layer that described the rates of release. In total, our results will guide the design of dynamic covalent hydrogels as biomaterials for drug delivery applications.
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http://dx.doi.org/10.1021/acs.biomac.0c00895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805009PMC
January 2021

Linking Molecular Behavior to Macroscopic Properties in Ideal Dynamic Covalent Networks.

J Am Chem Soc 2020 09 31;142(36):15371-15385. Epub 2020 Aug 31.

Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering, ETH Zurich, 8092 Zurich, Switzerland.

Dynamic covalent networks (DCvNs) are increasingly used in advanced materials design with applications ranging from recyclable thermosets to self-healing hydrogels. However, the relationship between the underlying chemistry at the junctions of DCvNs and their macroscopic properties is still not fully understood. In this work, we constructed a robust framework to predict how complex network behavior in DCvNs emerges from the chemical landscape of the dynamic chemistry at the junction. Ideal dynamic covalent boronic ester-based hydrogels were used as model DCvNs. We developed physical models that describe how viscoelastic properties, as measured by shear rheometry, are linked to the molecular behavior of the dynamic junction, quantified via fluorescence and NMR spectroscopy and DFT calculations. Additionally, shear rheometry was combined with Transition State Theory to quantify the kinetics and thermodynamics of network rearrangements, enabling a mechanistic understanding including preferred reaction pathways for dynamic covalent chemistries. We applied this approach to corroborate the "loose-bolt" postulate for the reaction mechanism in Wulff-type boronic acids. These findings, grounded in molecular principles, advance our understanding and rational design of dynamic polymer networks, improving our ability to predict, design, and leverage their unique properties for future applications.
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http://dx.doi.org/10.1021/jacs.0c06192DOI Listing
September 2020

Automated and Continuous Production of Polymeric Nanoparticles.

Front Bioeng Biotechnol 2019 17;7:423. Epub 2019 Dec 17.

Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering, ETH Zürich, Zurich, Switzerland.

Polymeric nanoparticles (NPs) are increasingly used as therapeutics, diagnostics, and building blocks in (bio)materials science. Current barriers to translation are limited control over NP physicochemical properties and robust scale-up of their production. Flow-based devices have emerged for controlled production of polymeric NPs, both for rapid formulation screening (~μg min) and on-scale production (~mg min). While flow-based devices have improved NP production compared to traditional batch processes, automated processes are desired for robust NP production at scale. Therefore, we engineered an automated coaxial jet mixer (CJM), which controlled the mixing of an organic stream containing block copolymer and an aqueous stream, for the continuous nanoprecipitation of polymeric NPs. The CJM was operated stably under computer control for up to 24 h and automated control over the flow conditions tuned poly(ethylene glycol)--polylactide (PEG --PLA ) NP size between ≈56 nm and ≈79 nm. In addition, the automated CJM enabled production of NPs of similar size ( ≈ 50 nm) from chemically diverse block copolymers, PEG --PLA , PEG--poly(lactide--glycolide) (PEG --PLGA ), and PEG--polycaprolactone (PEG --PCL ), by tuning the flow conditions for each block copolymer. Further, the automated CJM was used to produce model nanotherapeutics in a reproducible manner without user intervention. Finally, NPs produced with the automated CJM were used to scale the formation of injectable polymer-nanoparticle (PNP) hydrogels, without modifying the mechanical properties of the PNP gel. In conclusion, the automated CJM enabled stable, tunable, and continuous production of polymeric NPs, which are needed for the scale-up and translation of this important class of biomaterials.
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http://dx.doi.org/10.3389/fbioe.2019.00423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927919PMC
December 2019

Polymer-Nanoparticle Hydrogels.

Chimia (Aarau) 2019 Dec;73(12):1034

Department of Mechanical and Process Engineering, ETH Zurich, CH-8092 Zurich;, Email:

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http://dx.doi.org/10.2533/chimia.2019.1034DOI Listing
December 2019

Universal Nanocarrier Ink Platform for Biomaterials Additive Manufacturing.

Small 2019 12 25;15(51):e1905421. Epub 2019 Nov 25.

Sonneggstrasse 3, ETH Zürich, 8092, Zürich, Switzerland.

Ink engineering is a fundamental area of research within additive manufacturing (AM) that designs next-generation biomaterials tailored for additive processes. During the design of new inks, specific requirements must be considered, such as flowability, postfabrication stability, biointegration, and controlled release of therapeutic molecules. To date, many (bio)inks have been developed; however, few are sufficiently versatile to address a broad range of applications. In this work, a universal nanocarrier ink platform is presented that provides tailored rheology for extrusion-based AM and facilitates the formulation of biofunctional inks. The universal nanocarrier ink (UNI) leverages reversible polymer-nanoparticle interactions to form a transient physical network with shear-thinning and self-healing properties engineered for direct ink writing (DIW). The unique advantage of the material is that a range of functional secondary polymers can be combined with the UNI to enable stabilization of printed constructs via secondary cross-linking as well as customized biofunctionality for tissue engineering and drug delivery applications. Specific UNI formulations are used for bioprinting of living tissue constructs and DIW of controlled release devices. The robust and versatile nature of the UNI platform enables rapid formulation of a broad range of functional inks for AM of advanced biomaterials.
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http://dx.doi.org/10.1002/smll.201905421DOI Listing
December 2019

Injectable Polymer-Nanoparticle Hydrogels for Local Immune Cell Recruitment.

Biomacromolecules 2019 12 4;20(12):4430-4436. Epub 2019 Nov 4.

Department of Chemical and Biomolecular Engineering , University of Notre Dame , Notre Dame , Indiana 46556 , United States.

The ability to engineer immune function has transformed modern medicine, highlighted by the success of vaccinations and recent efforts in cancer immunotherapy. Further directions in programming the immune system focus on the design of immunomodulatory biomaterials that can recruit, engage with, and program immune cells locally in vivo. Here, we synthesized shear-thinning and self-healing polymer-nanoparticle (PNP) hydrogels as a tunable and injectable biomaterial platform for local dendritic cell (DC) recruitment. PNP gels were formed from two populations of poly(ethylene glycol)--polylactide (PEG--PLA) NPs with the same diameter but different PEG brush length (2 or 5 kDa). PEG--PLA NPs with the longer PEG brush exhibited improved gel formation following self-assembly and faster recovery after shear-thinning. In all cases, model protein therapeutics were released via Fickian diffusion in vitro, and minor differences in the release rate between the gel formulations were observed. PNP hydrogels were loaded with the DC cytokine CCL21 and injected subcutaneously in a murine model. CCL21-loaded PNP hydrogels recruited DCs preferentially to the site of injection in vivo relative to non-CCL21-loaded hydrogels. Thus, PNP hydrogels comprise a simple and tunable platform biomaterial for in vivo immunomodulation following minimally invasive subcutaneous injection.
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http://dx.doi.org/10.1021/acs.biomac.9b01129DOI Listing
December 2019

Injectable Biocompatible Hydrogels from Cellulose Nanocrystals for Locally Targeted Sustained Drug Release.

ACS Appl Mater Interfaces 2019 Oct 14;11(42):38578-38585. Epub 2019 Oct 14.

Injectable hydrogels from biocompatible materials are in demand for tissue engineering and drug delivery systems. Here, we produce hydrogels from mere cellulose nanocrystals (CNCs) by salt-induced charge screening. The injectability of CNC hydrogels was assessed by a combination of shear and capillary rheology, revealing that CNC hydrogels are conveyed via plug flow in capillaries allowing injection with minimal impact on mechanical properties. The potential of CNC hydrogels as drug carriers was elaborated by the in vitro release of the model protein bovine serum albumin (BSA), poorly water soluble tetracycline (TC), and readily soluble doxorubicin (DOX) into physiological saline and simulated gastric juice. For TC, a burst release was observed within 2 days, whereas BSA and DOX both showed a sustained release for 2 weeks. Only DOX was released fully from the hydrogels. The different release patterns were attributed to drug size, solubility, and specific drug-CNC interactions. The biocompatibility of CNC hydrogels and maintained bioactivity of released DOX were confirmed in a HeLa cell assay. The drug release was modulated by the incorporation of sucrose or xanthan gum in CNC hydrogels, whereas altering CNC concentration showed minor effects. The release into simulated gastric juice at pH 2 ceased for BSA due to charge inversion and electrostatic complexation, but not for smaller TC. Thus, CNC hydrogels may act as pH-responsive delivery systems that preserve drugs under gastric conditions followed by pH-triggered release in the duodenum.
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http://dx.doi.org/10.1021/acsami.9b15896DOI Listing
October 2019

Additive Manufacturing of Precision Biomaterials.

Adv Mater 2020 Apr 18;32(13):e1901994. Epub 2019 Aug 18.

Macromolecular Engineering Laboratory, Department of Mechanical and Process Engineering, ETH Zürich, 8092, Zürich, Switzerland.

Biomaterials play a critical role in modern medicine as surgical guides, implants for tissue repair, and as drug delivery systems. The emerging paradigm of precision medicine exploits individual patient information to tailor clinical therapy. While the main focus of precision medicine to date is the design of improved pharmaceutical treatments based on "-omics" data, the concept extends to all forms of customized medical care. This includes the design of precision biomaterials that are tailored to meet specific patient needs. Additive manufacturing (AM) enables free-form manufacturing and mass customization, and is a critical enabling technology for the clinical implementation of precision biomaterials. Materials scientists and engineers can contribute to the realization of precision biomaterials by developing new AM technologies, synthesizing advanced (bio)materials for AM, and improving medical-image-based digital design. As the field matures, AM is poised to provide patient-specific tissue and organ substitutes, reproducible microtissues for drug screening and disease modeling, personalized drug delivery systems, as well as customized medical devices.
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http://dx.doi.org/10.1002/adma.201901994DOI Listing
April 2020

Model Assisted Analysis of the Hepatic Arterial Buffer Response During Ex Vivo Porcine Liver Perfusion.

IEEE Trans Biomed Eng 2020 03 28;67(3):667-678. Epub 2019 May 28.

Objective: The hepatic arterial buffer response is a well-known phenomenon in hepatic circulation, describing the response of hepatic arterial resistance to changes in portal vein flow. Several vasoactive metabolites underlying its mechanism have been proposed, however, there is currently no clear consensus. The aim of this study is to investigate the hepatic arterial buffer response of porcine livers preserved in a controlled ex vivo perfusion machine.

Methods: Porcine livers are perfused on an ex vivo perfusion machine and hemodynamic experiments investigating the hepatic arterial resistance response to portal vein flow and vena cava pressure variations are conducted. A simple hemodynamic model is developed to support the interpretation of the received measurements. Further, a mechanism is proposed that explains hepatic arterial resistance changes in response to vena cava pressure as myogenic and in response to portal vein flow as a combined washout and myogenic effect.

Results: A clear correlation between hepatic sinusoidal pressure levels and hepatic arterial resistance is observed where an increase of approximately 4 mmHg of hepatic sinusoidal pressure level results in doubling of the hepatic arterial resistance. This relation is considered during the analysis of the portal vein flow variations resulting in a reduced isolated effect of adenosine washout on hepatic arterial resistance. With an average buffer capacity of 27% during our experiments, the hepatic arterial buffer response shows to be unimpaired in the ex vivo scenario.

Conclusion: First, washout and myogenic effects both influence the hepatic arterial buffer response; and second, hepatic sinusoidal pressure levels strongly influence the hepatic arterial resistance.

Significance: These results present new findings in hemodynamics of the liver, which are fundamental for successful ex vivo liver perfusion.
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http://dx.doi.org/10.1109/TBME.2019.2919413DOI Listing
March 2020

Immunofunctional photodegradable poly(ethylene glycol) hydrogel surfaces for the capture and release of rare cells.

Colloids Surf B Biointerfaces 2019 Feb 20;174:483-492. Epub 2018 Nov 20.

Department of Chemical Engineering, University of Wyoming, Laramie, WY 82071, United States. Electronic address:

Circulating tumor cells (CTCs) play a central role in cancer metastasis and represent a rich source of data for cancer prognostics and therapeutic guidance. Reliable CTC recovery from whole blood therefore promises a less invasive and more sensitive approach to cancer diagnosis and progression tracking. CTCs, however, are exceedingly rare in whole blood, making their quantitative recovery challenging. Several techniques capable of isolating these rare cells have been introduced and validated, yet most suffer from low CTC purity or viability, both of which are essential to develop a clinically viable CTC isolation platform. To address these limitations, we introduce a patterned, immunofunctional, photodegradable poly(ethylene glycol) (PEG) hydrogel capture surface for the isolation and selective release of rare cell populations. Flat and herringbone capture surfaces were successfully patterned via PDMS micromolding and photopolymerization of photolabile PEG hydrogels. Patterned herringbone surfaces, designed to convectively transport cells to the capture surface, exhibited improved capture density relative to flat surfaces for target cell capture from buffer, buffy coat, and whole blood. Uniquely, captured cells were released for collection by degrading the hydrogel capture surface with either bulk or targeted irradiation with cytocompatible doses of long wavelength UV light. Recovered cells remained viable following capture and release and exhibited similar growth rates as untreated control cells. The implementation of molded photodegradable PEG hydrogels as a CTC capture surface provides a micropatternable, cytocompatible platform that imparts the unique ability to recover pure, viable CTC samples by selectively releasing target cells.
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http://dx.doi.org/10.1016/j.colsurfb.2018.11.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545105PMC
February 2019

Matryoshka-Inspired Micro-Origami Capsules to Enhance Loading, Encapsulation, and Transport of Drugs.

Soft Robot 2019 02 20;6(1):150-159. Epub 2018 Nov 20.

1 Institute of Robotics and Intelligent Systems, ETH Zurich, Zurich, Switzerland.

Stimuli-responsive hydrogels are promising candidates for use in the targeted delivery of drugs using microrobotics. These devices enable the delivery and sustained release of quantities of drugs several times greater than their dry weight and are responsive to external stimuli. However, existing systems have two major drawbacks: (1) severe drug leakage before reaching the targeted areas within the body and (2) impeded locomotion through liquids due to the inherent hydrophilicity of hydrogels. This article outlines an approach to the assembly of hydrogel-based microcapsules in which one device is assembled within another to prevent drug leakage during transport. Inspired by the famous Russian stacking dolls (Matryoshka), the proposed scheme not only improves drug-loading efficiency but also facilitates the movement of hydrogel-based microcapsules driven by an external magnetic field. At room temperature, drug leakage from the hydrogel matrix is 90%. However, at body temperature the device folds up and assembles to encapsulate the drug, thereby reducing leakage to a mere 6%. The Matryoshka-inspired micro-origami capsule (MIMC) can disassemble autonomously when it arrives at a targeted site, where the temperature is slightly above body temperature. Up to 30% of the encapsulated drug was shown to diffuse from the hydrogel matrix within 1 h when it unfolds and disassembles. The MIMC is also shown to enhance the movement of magnetically driven microcapsules while navigating through media with a low Reynolds number. The translational velocity of the proposed MIMC (four hydrogel-based microcapsules) driven by magnetic gradients is more than three times greater than that of a conventional (single) hydrogel-based microcapsule.
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http://dx.doi.org/10.1089/soro.2018.0028DOI Listing
February 2019

Engineering a 3D-Bioprinted Model of Human Heart Valve Disease Using Nanoindentation-Based Biomechanics.

Nanomaterials (Basel) 2018 May 3;8(5). Epub 2018 May 3.

Center for Interdisciplinary Cardiovascular Sciences, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

In calcific aortic valve disease (CAVD), microcalcifications originating from nanoscale calcifying vesicles disrupt the aortic valve (AV) leaflets, which consist of three (biomechanically) distinct layers: the fibrosa, spongiosa, and ventricularis. CAVD has no pharmacotherapy and lacks in vitro models as a result of complex valvular biomechanical features surrounding resident mechanosensitive valvular interstitial cells (VICs). We measured layer-specific mechanical properties of the human AV and engineered a three-dimensional (3D)-bioprinted CAVD model that recapitulates leaflet layer biomechanics for the first time. Human AV leaflet layers were separated by microdissection, and nanoindentation determined layer-specific Young’s moduli. Methacrylated gelatin (GelMA)/methacrylated hyaluronic acid (HAMA) hydrogels were tuned to duplicate layer-specific mechanical characteristics, followed by 3D-printing with encapsulated human VICs. Hydrogels were exposed to osteogenic media (OM) to induce microcalcification, and VIC pathogenesis was assessed by near infrared or immunofluorescence microscopy. Median Young’s moduli of the AV layers were 37.1, 15.4, and 26.9 kPa (fibrosa/spongiosa/ventricularis, respectively). The fibrosa and spongiosa Young’s moduli matched the 3D 5% GelMa/1% HAMA UV-crosslinked hydrogels. OM stimulation of VIC-laden bioprinted hydrogels induced microcalcification without apoptosis. We report the first layer-specific measurements of human AV moduli and a novel 3D-bioprinted CAVD model that potentiates microcalcification by mimicking the native AV mechanical environment. This work sheds light on valvular mechanobiology and could facilitate high-throughput drug-screening in CAVD.
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http://dx.doi.org/10.3390/nano8050296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5977310PMC
May 2018

Surface tension-assisted additive manufacturing.

Nat Commun 2018 03 22;9(1):1184. Epub 2018 Mar 22.

The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main St Cambridge, Cambridge, MA, 02142, USA.

The proliferation of computer-aided design and additive manufacturing enables on-demand fabrication of complex, three-dimensional structures. However, combining the versatility of cell-laden hydrogels within the 3D printing process remains a challenge. Herein, we describe a facile and versatile method that integrates polymer networks (including hydrogels) with 3D-printed mechanical supports to fabricate multicomponent (bio)materials. The approach exploits surface tension to coat fenestrated surfaces with suspended liquid films that can be transformed into solid films. The operating parameters for the process are determined using a physical model, and complex geometric structures are successfully fabricated. We engineer, by tailoring the window geometry, scaffolds with anisotropic mechanical properties that compress longitudinally (~30% strain) without damaging the hydrogel coating. Finally, the process is amenable to high cell density encapsulation and co-culture. Viability (>95%) was maintained 28 days after encapsulation. This general approach can generate biocompatible, macroscale devices with structural integrity and anisotropic mechanical properties.
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http://dx.doi.org/10.1038/s41467-018-03391-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864961PMC
March 2018
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