3D hybrid wound devices for spatiotemporally controlled release kinetics

This paper presents localized and temporal control of releasekinetics over 3-dimensional (3D) hybridwounddevices to improve wound-healing process. Imaging study is performed to extract wound bed geometry in 3D. Non-Uniform Rational B-Splines (NURBS) based surface lofting is applied to generate functionally graded regions. Diffusion-based releasekinetics model is developed to predict time-based release of loaded modifiers for functionally graded regions. Multi-chamber single nozzle solid freeform dispensing system is used to fabricate wounddevices with controlled dispensing concentration. Spatiotemporal control of biological modifiers thus enables a way to achieve target delivery to improve wound healing

Trends in the design and use of elastin-like recombinamers as biomaterials

Producción CientíficaElastin-like recombinamers (ELRs), which derive from one of the repetitive domains found in natural elastin, have been intensively studied in the last few years from several points of view. In this mini review, we discuss all the recent works related to the investigation of ELRs, starting with those that define these polypeptides as model intrinsically disordered proteins or regions (IDPs or IDRs) and its relevance for some biomedical applications. Furthermore, we summarize the current knowledge on the development of drug, vaccine and gene delivery systems based on ELRs, while also emphasizing the use of ELR-based hydrogels in tissue engineering and regenerative medicine (TERM). Finally, we show different studies that explore applications in other fields, and several examples that describe biomaterial blends in which ELRs have a key role. This review aims to give an overview of the recent advances regarding ELRs and to encourage further investigation of their properties and applications.Comisión Europea (project NMP-2014-646075)Ministerio de Economía, Industria y Competitividad (projects PCIN-2015-010 / MAT2016-78903-R / BES-2014-069763)Junta de Castilla y León (project VA317P18

Natural materials

The use of naturally occurring materials as scaffolds to support cell growth and proliferation significantly impacted the origin and progress of tissue engineering and regenerative medicine. However, the majority of these materials failed to provide adequate cues to guide cell differentiation toward the formation of new tissues. Over the past decade, a new generation of multifunctional and smart natural-based materials has been developed to provide biophysical and biochemical cues intended to specifically guide cell behavior. In this chapter, the use of extracellular matrix proteins and blood-derivatives intrinsic capacity to mimic the biophysical and biological characteristics of native tissues is reviewed. Furthermore, the design of a variety of nanostructures using the well-explored characteristics of nucleic acids is summarized. In the second section, the exploitation of supramolecular chemistry to create new dynamic functional hydrogels that mimic the extracellular matrix structure and/or composition is surveyed. Then, the incorporation of nanoelements in polymeric networks for the design of smart nanocomposite materials with tailored functionalities to guide cell behavior is introduced. Finally, the future perspectives in the development of new biomaterials for tissue engineering and regenerative medicine are presented.Te authors acknowledge the fnancial support of the European Union Framework Programme for Research and Innovation Horizon 2020, under the TEAMING grant agreement No 739572 – Te Discoveries CTR, Marie Skłodowska-Curie grant agreement No 706996 and European Research Council grant agreement No 726178; FCT (Fundação para a Ciência e a Tecnologia) and the Fundo Social Europeu através do Programa Operacional do Capital Humano (FSE/POCH) in the framework of Ph.D. grants PD/BD/113807/2015 (BBM) and PD/BD/129403/2017 (SMB), Post-Doc grant SFRH/ BPD/112459/2015 (RMD) and project SmarTendon (PTDC/NAN-MAT/30595/2017); Project NORTE01-0145-FEDER-000021 supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF

Design of Bio-Conjugated Hydrogels for Regenerative Medicine Applications: From Polymer Scaffold to Biomolecule Choice

Bio-conjugated hydrogels merge the functionality of a synthetic network with the activity of a biomolecule, becoming thus an interesting class of materials for a variety of biomedical applications. This combination allows the fine tuning of their functionality and activity, whilst retaining biocompatibility, responsivity and displaying tunable chemical and mechanical properties. A complex scenario of molecular factors and conditions have to be taken into account to ensure the correct functionality of the bio-hydrogel as a scaffold or a delivery system, including the polymer backbone and biomolecule choice, polymerization conditions, architecture and biocompatibility. In this review, we present these key factors and conditions that have to match together to ensure the correct functionality of the bio-conjugated hydrogel. We then present recent examples of bio-conjugated hydrogel systems paving the way for regenerative medicine applications

Photodeagradable hydrogels for tissue gluing

Hydrogel biomaterials for wound care dressing and tissue gluing need to adhere to tissue and on-demand disappear. Advanced tissue adhesives also envision the encapsulation of therapeutic drugs or cells to promote the healing process. The design of hydrogels with all these functionalities is challenging. In this PhD, hydrogels that fulfil several of the previous properties for wound dressing at reasonable chemical complexity is presented. These hydrogels can be formed in situ and encapsulate cells, they can adhere to tissue and detach after use by light exposure at cytocompatible doses. The developed photodegradable hydrogels are based on 4-star PEG end-catechol precursors for crosslinking, and intercalate photocleavable o-nitrobenzyl groups in their structure. These gels can form at mild oxidative conditions and encapsulate cells or microparticles. UV-vis light exposure (λ= 365 or 405 nm) photocleavables the nitrobenzyl moiety and promotes degradation. This can occur at cytocompatible doses, and enables on-demand detachment from tissue and release of the encapsulated materials or cells. These biomaterials are interesting for the development of advanced tissue adhesives and cell therapies, by expanding the range of functionality of existing choices.Die entwickelten photodegradierbaren Hydrogele basieren auf 4-Stern-PEG, das in dieser Arbeit chemisch mit endständigen Catecholgruppen und photospaltbaren o-Nitrobenzylgruppen modifiziert wurde. Die Vernetzung erfolgt über die Catecholgruppen unter oxidativen Bedingungen in HEPES-Puffer mit 9-18 mM Natriumperiodat als Oxidationsmittel. Diese Bedingungen sind mild genug, um lebende Zellen oder Mikropartikeln in das Material einzubetten. Bei Belichtung mit UV (λ 365 nm) oder sichtbarem Licht (λ 405 nm) in zytokompatiblen Lichtdosen fördert die photospaltbare Nitrobenzyleinheit den Hydrogelabbau, was die on-demand Freisetzung von Zellen und das Ablösen vom Gewebe ermöglicht. Diese Biomaterialien sind interessant für die Entwicklung fortschrittlicher Gewebeklebstoffe und Zelltherapien, und erweitern den Funktionsumfang gegenüber bisherigen Auswahlmöglichkeiten.The research presented in this doctoral thesis has been performed at the INM-Leibniz- Institute for New Materials (Saarbrücken) and was funded by the European Union within the Marie Sklodowska-Curie Innovative Training School (BioSmartTrainee, Project No. 642861)

Mechanoresponsive drug delivery: harnessing forces for controlled release

Mechanically-activated delivery systems harness existing physiological and/or externally-applied forces to provide spatiotemporal control over the release of active agents. The presence and necessity of these forces in the human body and in the increasing use of mechanically-driven medical devices (e.g., stents, balloon catheters, gastric bands, tissue expanders) can serve as functional dynamic triggers. Therefore, this dissertation investigates the use of applied tensile strain and cyclic loading to control release of entrapped agents, and further translates the concept towards clinical applications by integrating the system with commercial medical devices that provide precise forces to trigger release. As an initial proof-of-concept, mechanoresponsive composites, consisting of highly-textured superhydrophobic barrier coatings over a hydrophilic substrate, are fabricated. The release of entrapped agents, controlled by the magnitude of applied strain, results in a graded response due to water infiltration through propagating patterned cracks in the coating. The strain-dependent delivery of anticancer agents with in vitro efficacy as well as the ex vivo delivery to esophageal tissue with an integrated stent system are demonstrated. Release is further modulated by barrier coating properties. Thicker coatings afford slower release rates with preserved in vitro activity for both a chemotherapeutic and an enzyme. Localizing coating crack patterns based on different geometric stress concentration factors further controls the selective sequential release of multiple agents. Finally, the development of a reversible mechanoresponsive system is investigated to provide cycle-mediated pulsatile release. Optimization of mechanical parameters results in delivery of multiple doses. To translate this concept towards the clinic, the system is integrated with commercial balloon catheters to provide multidose delivery of small molecules to ex vivo vessels. Using the inherent inflation and deflation of the catheter to trigger release, the system enhances existing capabilities to treat cardiovascular and peripheral artery diseases. In summary, the development of mechanoresponsive systems that respond to tensile strain and cycle number are described for the delivery of a wide-range of active agents (hydrophilic and hydrophobic small molecules as well as an enzyme), and their integration with existing medical devices. Furthermore, the comprehensive range of specific kinetic profiles, including triggered release, pulsatile delivery, and the sequential delivery of multiple agents, showcases the capabilities and versatility of these dynamic mechanoresponsive systems to modulate release for the treatment of various clinical diseases.2019-02-20T00:00:00

Natural-origin materials for tissue engineering and regenerative medicine

Recent advances in tissue engineering and regenerative medicine have shown that combining biomaterials, cells, and bioactive molecules are important to promote the regeneration of damaged tissues or as therapeutic systems. Natural origin polymers have been used as matrices in such applications due to their biocompatibility and biodegradability. This article provides an up-to-date review on the most promising natural biopolymers, focused on polysaccharides and proteins, their properties and applications. Membranes, micro/nanoparticles, scaffolds, and hydrogels as biomimetic strategies for tissue engineering and processing are described, along with the use of bioactive molecules and growth factors to improve tissue regeneration potential. Finally, current biomedical applications are also presented.The authors would like to thank to the financial support from the Portuguese Foundation for Science and Technology (FCT) for the fellowship grants of Simone S Silva (SFRH/BPD/112140/2015), Emanuel M Fernandes (SFRH/BPD/96197/2013), Joana-Silva Correira (SFRH/BPD/100590/2014), Sandra Pina (SFRH/BPD/108763/2015), Silvia Vieira (SFRH/BD/102710/2014), “Fundo Social Europeu”- FSE and “ Programa Diferencial de Potencial Humano POPH”, and to the distinction attributed to J.M. Oliveira under the Investigator FCT program (IF/00423/2012). It is also greatly acknowledged the funds provided by FCT through the project EPIDisc (UTAP-EXPL/BBBECT/0050/2014), financed in the Framework of the “International Collaboratory for Emerging Technologies, CoLab”, UT Austin|Portugal Program.info:eu-repo/semantics/publishedVersio

DEVELOPMENT OF NANOPARTICLE RATE-MODULATING AND SYNCHROTRON PHASE CONTRAST-BASED ASSESSMENT TECHNIQUES FOR CARDIAC TISSUE ENGINEERING

Myocardial infarction (MI) is the most common cause of heart failure. Despite advancements in cardiovascular treatments and interventions, current therapies can only slow down the progression of heart failure, but not tackle the progressive loss of cardiomyocytes after MI. One aim of cardiac tissue engineering is to develop implantable constructs (e.g. cardiac patches) that provide physical and biochemical cues for myocardium regeneration. To this end, vascularization in these constructs is of great importance and one key issue involved is the spatiotemporal control of growth-factor (GF)-release profiles. The other key issue is to non-invasively quantitatively monitor the success of these constructs in-situ, which will be essential for longitudinal assessments as studies are advanced from ex-vivo to animal models and human patients. To address these issues, the present research aims to develop nanoparticles to modulate the temporal control of GF release in cardiac patches, and to develop synchrotron X-ray phase contrast tomography for visualization and quantitative assessment of 3D-printed cardiac patch implanted in a rat MI model, with four specific objectives presented below. The first research objective is to optimize nanoparticle-fabrication process in terms of particle size, polydispersity, loading capacity, zeta potential and morphology. To achieve this objective, a comprehensive experimental study was performed to examine various process parameters used in the fabrication of poly(lactide-co-glycolide) (PLGA) nanoparticles, along with the development of a novel computational approach for the nanoparticle-fabrication optimization. Results show that among various process parameters examined, the polymer and the external aqueous phase concentrations are the most significant ones to affect the nanoparticle physical and release characteristics. Also, the limitations of PLGA nanoparticles such as initial burst effect and the lack of time-delayed release patterns are identified. The second research objective is to develop bi-layer nanoparticles to achieve the controllable release of GFs, meanwhile overcoming the above identified limitations of PLGA nanoparticles. The bi-layer nanoparticle is composed of protein-encapsulating PLGA core and poly(L-lactide) (PLLA)-rate regulating shell, thus allowing for low burst effect, protein structural integrity and time-delayed release patterns. The bi-layer nanoparticles, along with PLGA ones, were successfully fabricated and then used to regulate simultaneous and/or sequential release of multiple angiogenic factors with the results demonstrating that they are effective to promote angiogenesis in fibrin matrix. The third objective is to develop novel mathematical models to represent the controlled-release of bioactive agents from nanoparticles. For this, two models, namely the mechanistic model and geno-mechanistic model, were developed based on the local and global volume averaging approaches, respectively, and then validated with experiments on both single- and bi-layer nanoparticles, by which the ovalbumin was used as a protein model for the release examination. The results illustrates the developed models are able to provide insight on the release mechanism and to predict nanoparticle transport and degradation properties of nanoparticles, thus providing a means to regulate and control the release of bioactive agents from the nanoparticles for tissue engineering applications. The fourth objective of this research is to develop a synchrotron-based phase contrast non-invasive imaging technique for visualization and quantitative assessment of cardiac patch implanted in a rat MI model. To this end, the patches were created from alginate strands using the three-dimensional (3D) printing technique and then surgically implanted on rat hearts for the assessment based on phase contrast tomography. The imaging of samples was performed at various sample-to-detector distances, CT-scan time, and areas of the region of interest (ROI) to examine their effects on imaging quality. Phase-retrieved images depict visible and quantifiable structural details of the patch at low radiation dose, which, however, are not seen from the images by means of dual absorption-phase and a 3T clinical magnetic resonance imaging. Taken together, this research represents a significant advance in cardiac tissue engineering by developing novel nano-guided approaches for vascularization in myocardium regeneration as well as non-invasive and quantitative monitoring techniques for longitudinal studies on the cardiac patch implanted in animal model and eventually in human patients