An Electrical Stimulation Device For In Vitro Neural Engineering.

Due to the intrinsically low turnover of neural tissues, regenerative therapies have gained significant interest in the context of degenerative diseases and injury to the central and peripheral nervous systems. Although a range of neuroregenerative strategies involving cell transplants and drugs have been explored, these are often limited by low efficacy and unwanted side effects. Electrical stimulation (ES) is thought to modulate the proliferation and differentiation of neural stem cells (NSCs), and thus it represents a promising strategy for neuroregenerative therapies. However, its influence on the biology of endogenous and exogenous NSCs, and the effect of different stimulation paradigms remains unexplored. Additionally, the variability of stimulation platforms and parameters employed in previous studies prevents reliable and reproducible discoveries. Therefore, there is a need to develop versatile and robust tools to study the effect of electrical stimulation on NSC fate in vitro. This paper outlines the development and functional application of a standardised, electrically stable, and easily reproducible ES platform for in vitro neuroregeneration applications.Clinical Relevance- The elucidation of the cellular and molecular mechanisms underlying the effect of ES paradigms on NSCs proliferation and differentiation holds great potential for the development of neuroregenerative therapies.

A Pilot In Vivo Study of Flexible Fully Polymeric Nerve Cuff Electrodes.

Recent trends in the field of bioelectronics have been focused on the development of electrodes that facilitate safe and efficient stimulation of nervous tissues. Novel conducting polymer (CP) based materials, such as flexible and fully polymeric conductive elastomers (CEs), constitute a promising alternative to improve on the limitations of current metallic devices. This pilot study demonstrates the performance of tripolar CE-based peripheral nerve cuffs compared to current commercial tripolar platinum-iridium (PtIr) nerve cuffs in vivo. CE and metallic cuff devices were implanted onto rodent sciatic nerves for a period of 8 weeks. Throughout the entire study, the CE device demonstrated improved charge transfer and electrochemical safety compared to the PtIr cuff, able to safely inject 2 to 3 times more charge. In comparison to the commercial control, the CE cuff was able to record in the in vivo setting with reduced noise and produced smaller voltages at all simulation levels. CE technologies provide a promising alternative to metallic devices for the development of bioelectronics with enhanced chronic device functionality.

Biohybrid neural interfaces: improving the biological integration of neural implants.

Implantable neural interfaces (NIs) have emerged in the clinic as outstanding tools for the management of a variety of neurological conditions caused by trauma or disease. However, the foreign body reaction triggered upon implantation remains one of the major challenges hindering the safety and longevity of NIs. The integration of tools and principles from biomaterial design and tissue engineering has been investigated as a promising strategy to develop NIs with enhanced functionality and performance. In this Feature Article, we highlight the main bioengineering approaches for the development of biohybrid NIs with an emphasis on relevant device design criteria. Technical and scientific challenges associated with the fabrication and functional assessment of technologies composed of both artificial and biological components are discussed. Lastly, we provide future perspectives related to engineering, regulatory, and neuroethical challenges to be addressed towards the realisation of the promise of biohybrid neurotechnology.

The influence of background music and narrative setting on anthropomorphic judgements of killer whale (Orcinus orca) emotional states and subsequent donation behavior.

Animal documentary films such as Blackfish, considered nonfiction accounts of reality, nonetheless use rhetorical devices to engage viewers and shape their emotional experience for maximum effect. Such devices can also influence attitudes and alter behavior. In animal documentaries, anthropomorphic impressions of the animals by audiences are key. Using general population samples in the US, three online experiments assessed the influence of background music and narrative setting on how viewers emotionally appraised the emotional state of a killer whale (Orcinus orca) and subsequently donated to causes affiliated with killer whales. While happy music led to perceptions of a happy whale, sad music led to perceptions of a sad whale. mediation analyses showed that these perceptions indirectly influence donation behavior, via beliefs about the killer whale's welfare and wellbeing. Analyses also indicated that the highest donation amounts towards killer whales were elicited from footage depicting a killer whale in the wild, with sad background music. These findings highlight the potential power that animal and nature documentaries have over viewers, which, when combined with human tendencies toward anthropomorphism, can have significant influence on conservation attitudes and behavior.

Factors Affecting Dental Students' Comfort with Online Synchronous Learning.

Background: The COVID-19 pandemic caused many universities to expand their use of videoconferencing technology to continue academic coursework. This study examines dental students' experience, comfort levels, and preferences with videoconferencing. Methods: Of 100 s-year US dental students enrolled in a local anesthesia course, 54 completed a survey following an online synchronous lecture given in August 2020. Survey questions asked about prior experience with videoconferencing, comfort levels with online and traditional classes, and reasons for not turning on their video (showing their face). Results: Overall, 48.2% had little or no experience with videoconferencing prior to March 2020. Students were more comfortable with in-classroom parameters (listening, asking questions, answering questions, and interacting in small groups (breakouts)) than with online synchronous learning, although differences were not significant (p's > 0.10). Regression analyses showed there were significant positive associations between videoconferencing experience and comfort with both answering questions and interacting in breakouts (B = 0.55, p = 0.04 and B = 0.54, p = 0.03, respectively). Students reported being more comfortable during in-classroom breakouts than in breakouts using videoconferencing (p = 0.003). Main reasons for students not turning on their cameras were that they did not want to dress up (48.1%), other students were not using their video features (46.3%), and they felt they did not look good (35.5%). Conclusions: Dental students were somewhat more comfortable with traditional in-person vs. online classroom parameters. Prior experience with videoconferencing was associated with increased comfort with synchronous learning, suggesting that after the pandemic, it may be beneficial to structure dental school curricula as a hybrid learning experience with both in-person and online synchronous courses.

The influence of physicochemical properties on the processibility of conducting polymers: A bioelectronics perspective.

Conducting polymers (CPs) possess unique electrical and electrochemical properties and hold great potential for different applications in the field of bioelectronics. However, the widespread implementation of CPs in this field has been critically hindered by their poor processibility. There are four key elements that determine the processibility of CPs, which are thermal tunability, chemical stability, solvent compatibility and mechanical robustness. Recent research efforts have focused on enhancing the processibility of these materials through pre- or post-synthesis chemical modifications, the fabrication of CP-based complexes and composites, and the adoption of additive manufacturing techniques. In this review, the physicochemical and structural properties that underlie the performance and processibility of CPs are examined. In addition, current research efforts to overcome technical limitations and broaden the potential applications of CPs in bioelectronics are discussed. STATEMENT OF SIGNIFICANCE: This review details the inherent properties of CPs that have hindered their use in additive manufacturing for the creation of 3D bioelectronics. A fundamental approach is presented with consideration of the chemical structure and how this contributes to their electrical, thermal and mechanical properties. The review then considers how manipulation of these properties has been addressed in the literature including areas where improvements can be made. Finally, the review details the use of CPs in additive manufacturing and the future scope for the use of CPs and their composites in the development of 3D bioelectronics.

Adaptive biomimicry: design of neural interfaces with enhanced biointegration.

Neural interfaces (NIs) have traditionally used inorganic device constructs paired with electrical stimulation to bypass injured or diseased electroactive tissues. These bioinert devices have significant impact on the neural tissue, being synthetic and causing large volumetric changes to the biological environment. The concept of biomimicry has become popular for tissue engineering technologies, reflecting biological properties as a component of material design. Tissue engineering strategies can be harnessed in bioelectronic device design to improve biological tolerance, but the need for improved integration with the native tissue remains an unmet need. Adaptive biomimetic designs that respond to the changing neural tissue environment associated with wound healing can actively address the immune response to improve biointegration. These adaptive approaches include responsive materials paired with stem cells and bioactive molecules as integrated components of NIs. Combining adaptive biomimetics with NIs provides a new, more natural approach for communicating with the nervous system.

Mind the gap: State-of-the-art technologies and applications for EEG-based brain-computer interfaces.

Brain-computer interfaces (BCIs) provide bidirectional communication between the brain and output devices that translate user intent into function. Among the different brain imaging techniques used to operate BCIs, electroencephalography (EEG) constitutes the preferred method of choice, owing to its relative low cost, ease of use, high temporal resolution, and noninvasiveness. In recent years, significant progress in wearable technologies and computational intelligence has greatly enhanced the performance and capabilities of EEG-based BCIs (eBCIs) and propelled their migration out of the laboratory and into real-world environments. This rapid translation constitutes a paradigm shift in human-machine interaction that will deeply transform different industries in the near future, including healthcare and wellbeing, entertainment, security, education, and marketing. In this contribution, the state-of-the-art in wearable biosensing is reviewed, focusing on the development of novel electrode interfaces for long term and noninvasive EEG monitoring. Commercially available EEG platforms are surveyed, and a comparative analysis is presented based on the benefits and limitations they provide for eBCI development. Emerging applications in neuroscientific research and future trends related to the widespread implementation of eBCIs for medical and nonmedical uses are discussed. Finally, a commentary on the ethical, social, and legal concerns associated with this increasingly ubiquitous technology is provided, as well as general recommendations to address key issues related to mainstream consumer adoption.

Development and implementation of a patient assistance fund: a descriptive study.

BACKGROUND: The purpose of this descriptive study is to outline the Roseman University of Health Sciences (RUHS) College of Dental Medicines' Patient Assistance Fund development, organization and outcomes. The description and reported results provide insight to others considering similar health professions programs. METHODS: The Patient Assistance Fund (PAF) affords dental students an opportunity to petition for and obtain financial assistance for their most disadvantaged patients. In this study, two sources of data were collected and used with a quantitative analysis for data collected as part of the PAFs operation and a qualitative analysis to evaluate the patient experiences. RESULTS: A total of 16 student advocates, consisting of 6 males and 10 females from the D3 and D4 classes made 26 presentations to the PAF board committee. The combined amount requested from the PAF was $47,428.00 ("Cost of Treatment Plan") representing an average request per patient of $1824.15 (range $324.00 to $4070.00). The approved procedures and treatment plans totaled $21,278.36 ("Cost of Approved Procedures") with an average of $818.40 (range $204.00 to $2434.00) per patient. Patients and students expressed a high degree of satisfaction with the program. CONCLUSIONS: This study provides an overview of the structure, funding sources, expenditures and patient services supported by a dental student managed patient assistance fund. The experiences at RUHS College of Dental Medicine (CODM) suggest that other healthcare professions schools can develop similar type programs that yield benefit both to students and to patients in need.

Gelatin Methacryloyl Bioadhesive Improves Survival and Reduces Scar Burden in a Mouse Model of Myocardial Infarction.

Background Delivery of hydrogels to the heart is a promising strategy for mitigating the detrimental impact of myocardial infarction (MI). Challenges associated with the in vivo delivery of currently available hydrogels have limited clinical translation of this technology. Gelatin methacryloyl (GelMA) bioadhesive hydrogel could address many of the limitations of available hydrogels. The goal of this proof-of-concept study was to evaluate the cardioprotective potential of GelMA in a mouse model of MI. Methods and Results The physical properties of GelMA bioadhesive hydrogel were optimized in vitro. Impact of GelMA bioadhesive hydrogel on post-MI recovery was then assessed in vivo. In 20 mice, GelMA bioadhesive hydrogel was applied to the epicardial surface of the heart at the time of experimental MI. An additional 20 mice underwent MI but received no GelMA bioadhesive hydrogel. Survival rates were compared for GelMA-treated and untreated mice. Left ventricular function was assessed 3 weeks after experimental MI with transthoracic echocardiography. Left ventricular scar burden was measured with postmortem morphometric analysis. Survival rates at 3 weeks post-MI were 89% for GelMA-treated mice and 50% for untreated mice (P=0.011). Left ventricular contractile function was better in GelMA-treated than untreated mice (fractional shortening 37% versus 26%, P<0.001). Average scar burden in GelMA-treated mice was lower than in untreated mice (6% versus 22%, P=0.017). Conclusions Epicardial GelMA bioadhesive application at the time of experimental MI was performed safely and was associated with significantly improved post-MI survival compared with control animals. In addition, GelMA treatment was associated with significantly better preservation of left ventricular function and reduced scar burden.

Synthesis and characterization of osteoinductive visible light-activated adhesive composites with antimicrobial properties.

Orthopedic surgical procedures based on the use of conventional biological graft tissues are often associated with serious post-operative complications such as immune rejection, bacterial infection, and poor osseointegration. Bioresorbable bone graft substitutes have emerged as attractive alternatives to conventional strategies because they can mimic the composition and mechanical properties of the native bone. Among these, bioactive glasses (BGs) hold great potential to be used as biomaterials for bone tissue engineering owing to their biomimetic composition and high biocompatibility and osteoinductivity. Here, we report the development of a novel composite biomaterial for bone tissue engineering based on the incorporation of a modified strontium- and lithium-doped 58S BG (i.e., BG-5/5) into gelatin methacryloyl (GelMA) hydrogels. We characterized the physicochemical properties of the BG formulation via different analytical techniques. Composite hydrogels were then prepared by directly adding BG-5/5 to the GelMA hydrogel precursor, followed by photocrosslinking of the polymeric network via visible light. We characterized the physical, mechanical, and adhesive properties of GelMA/BG-5/5 composites, as well as their in vitro cytocompatibility and osteoinductivity. In addition, we evaluated the antimicrobial properties of these composites in vitro, using a strain of methicillin-resistant Staphylococcus Aureus. GelMA/BG-5/5 composites combined the functional characteristics of the inorganic BG component, with the biocompatibility, biodegradability, and biomimetic composition of the hydrogel network. This novel biomaterial could be used for developing osteoinductive scaffolds or implant surface coatings with intrinsic antimicrobial properties and higher therapeutic efficacy.

An Antimicrobial Dental Light Curable Bioadhesive Hydrogel for Treatment of Peri-Implant Diseases.

Dental implants constitute the standard of care to replace the missing teeth, which has led to an increase in the number of patients affected by peri-implant diseases (PIDs). Here, we report the development of an antimicrobial bioadhesive, GelAMP, for the treatment of PIDs. The hydrogel is based on a visible light-activated naturally-derived polymer (gelatin) and an antimicrobial peptide (AMP). The optimized formulation of GelAMP could be rapidly crosslinked using commercial dental curing systems. When compared to commercial adhesives, the bioadhesives exhibited significantly higher adhesive strength to physiological tissues and titanium. Moreover, the bioadhesive showed high cytocompatibility and could efficiently promote cell proliferation and migration in vitro. GelAMP also showed remarkable antimicrobial activity against Porphyromonas gingivalis. Furthermore, it could support the growth of autologous bone after sealing calvarial bone defects in mice. Overall, GelAMP could be used as a platform for the development of more effective therapeutics against PIDs.

Local Immunomodulation Using an Adhesive Hydrogel Loaded with miRNA-Laden Nanoparticles Promotes Wound Healing.

Chronic wounds are characterized by impaired healing and uncontrolled inflammation, which compromise the protective role of the immune system and may lead to bacterial infection. Upregulation of miR-223 microRNAs (miRNAs) shows driving of the polarization of macrophages toward the anti-inflammatory (M2) phenotype, which could aid in the acceleration of wound healing. However, local-targeted delivery of microRNAs is still challenging, due to their low stability. Here, adhesive hydrogels containing miR-223 5p mimic (miR-223*) loaded hyaluronic acid nanoparticles are developed to control tissue macrophages polarization during wound healing processes. In vitro upregulation of miR-223* in J774A.1 macrophages demonstrates increased expression of the anti-inflammatory gene Arg-1 and a decrease in proinflammatory markers, including TNF-α, IL-1ß, and IL-6. The therapeutic potential of miR-223* loaded adhesive hydrogels is also evaluated in vivo. The adhesive hydrogels could adhere to and cover the wounds during the healing process in an acute excisional wound model. Histological evaluation and quantitative polymerase chain reaction (qPCR) analysis show that local delivery of miR-223* efficiently promotes the formation of uniform vascularized skin at the wound site, which is mainly due to the polarization of macrophages to the M2 phenotype. Overall, this study demonstrates the potential of nanoparticle-laden hydrogels conveying miRNA-223* to accelerate wound healing.

Systematic review and meta-analysis of the efficacy and safety of leflunomide and methotrexate in the treatment of rheumatoid arthritis / Revisión sistemática y metaanálisis de la eficacia y la seguridad de leflunomida y metotrexato en el tratamiento de la artritis reumatoide

Objective: To assess the efficacy and side effects of methotrexate and leflunomide in patients with rheumatoid arthritis (RA) as the first disease-modifying antirheumatic drug (DMARD). Methods: We performed a systematic review and meta-analysis of clinical studies that included patients who took methotrexate, leflunomide, placebo or another DMARD for RA treatment. A systematic review yielded 1971 articles from databases; once completely reviewed, 73 trials that completed inclusion criteria were selected. In structured workshops for discussion and assessment of each article, 6 could be meta-analyzed for the primary and secondary outcomes: achievement of American College of Rheumatology (ACR) 20 and its core set components; and change of serum C-reactive protein (CRP) levels, Health Assessment Questionnaire Disability Index (HAQ-Di), liver enzyme aspartate transaminase/alanine transaminase ratio, new gastrointestinal (GI) side effects and infections. Results: A total of 1984 patients were included: 986 took leflunomide and 998 methotrexate. The probability of achieving ACR 20 had an odds ratio (OR) of 0.88 (95% confidence interval [CI] 0.74, 1.06) with a trend toward favoring methotrexate; reduction of the swollen joint count was greater for methotrexate: mean difference=0.82 (95%CI 0.24, 1.39); tender joint count, physician global assessment, HAQ-Di, and serum CRP levels revealed no significant difference between groups. Increased liver enzymes were more frequent in the leflunomide group, OR=0.38 (95%CI 0.27, 0.53), and new GI complaints were more common with methotrexate (OR=1.44; 95%CI 1.17, 1.79). There was no difference in the incidence of non-severe infections. Conclusion: Leflunomide used as the first DMARD in RA seemed to be as efficacious as methotrexate; only the reduction of swollen joint count was more marked for methotrexate. Leflunomide was linked to a greater increase in liver enzymes, but there were fewer GI complaints

Objetivo: Evaluar la eficacia y los efectos secundarios del metotrexato o la leflunomida en pacientes con AR como primer fármaco modificador de la enfermedad (FAME). Métodos: Se realizó una revisión sistemática y metaanálisis de estudios clínicos que incluyeron a pacientes que tomaron metotrexato, leflunomida, placebo u otro FAME para el tratamiento de la AR. Después de una revisión sistemática, se encontraron 1.971 artículos, una vez revisados completamente, se seleccionaron 73 ensayos que completaron los criterios de inclusión. En talleres estructurados para el debate y la evaluación de cada artículo, 6 pudieron ser metaanalizados para los resultados primarios y secundarios: logro de ACR 20 y sus componentes básicos, así como el cambio de los niveles séricos de PCR, HAQ-DI, enzimas hepáticas AST/ALT, nuevos efectos secundarios gastrointestinales (GI) e infecciones. Resultados: Se incluyó a un total de 1.984 pacientes, 986 tomaron leflunomida y 998 metotrexato. La probabilidad de alcanzar ACR 20 reveló una OR 0,88 (IC del 95%: 0,74; 1,06) con una tendencia a favorecer el metotrexato; la reducción del recuento de articulaciones inflamadas fue mayor para metotrexato: diferencia de medias (MD)=0,82 (IC del 95%: 0,24, 1,39); el recuento de articulaciones sensibles, la evaluación global de médicos, el HAQ-DI, y los niveles séricos de PCR no revelaron diferencias entre los grupos. El aumento de las enzimas hepáticas fue más frecuente en el grupo con leflunomida, OR=0,38 (IC del 95%: 0,27, 0,53) y las nuevas quejas GI fueron más frecuentes en el metotrexato, OR=1,44 (IC del 95% 1,17, 1,79). No hubo diferencias en la incidencia de infecciones no graves. Conclusión: La leflunomida utilizada como el primer FAME en la AR parece ser tan eficaz como el metotrexato; solo la reducción de las articulaciones inflamadas fue mayor para el metotrexato. La leflunomida está relacionada con una mayor elevación de las enzimas hepáticas, pero presenta menos molestias GI

Engineering a naturally-derived adhesive and conductive cardiopatch.

Myocardial infarction (MI) leads to a multi-phase reparative process at the site of damaged heart that ultimately results in the formation of non-conductive fibrous scar tissue. Despite the widespread use of electroconductive biomaterials to increase the physiological relevance of bioengineered cardiac tissues in vitro, there are still several limitations associated with engineering biocompatible scaffolds with appropriate mechanical properties and electroconductivity for cardiac tissue regeneration. Here, we introduce highly adhesive fibrous scaffolds engineered by electrospinning of gelatin methacryloyl (GelMA) followed by the conjugation of a choline-based bio-ionic liquid (Bio-IL) to develop conductive and adhesive cardiopatches. These GelMA/Bio-IL adhesive patches were optimized to exhibit mechanical and conductive properties similar to the native myocardium. Furthermore, the engineered patches strongly adhered to murine myocardium due to the formation of ionic bonding between the Bio-IL and native tissue, eliminating the need for suturing. Co-cultures of primary cardiomyocytes and cardiac fibroblasts grown on GelMA/Bio-IL patches exhibited comparatively better contractile profiles compared to pristine GelMA controls, as demonstrated by over-expression of the gap junction protein connexin 43. These cardiopatches could be used to provide mechanical support and restore electromechanical coupling at the site of MI to minimize cardiac remodeling and preserve normal cardiac function.

Systematic review and meta-analysis of the efficacy and safety of leflunomide and methotrexate in the treatment of rheumatoid arthritis.

OBJECTIVE: To assess the efficacy and side effects of methotrexate and leflunomide in patients with rheumatoid arthritis (RA) as the first disease-modifying antirheumatic drug (DMARD). METHODS: We performed a systematic review and meta-analysis of clinical studies that included patients who took methotrexate, leflunomide, placebo or another DMARD for RA treatment. A systematic review yielded 1971 articles from databases; once completely reviewed, 73 trials that completed inclusion criteria were selected. In structured workshops for discussion and assessment of each article, 6 could be meta-analyzed for the primary and secondary outcomes: achievement of American College of Rheumatology (ACR) 20 and its core set components; and change of serum C-reactive protein (CRP) levels, Health Assessment Questionnaire Disability Index (HAQ-Di), liver enzyme aspartate transaminase/alanine transaminase ratio, new gastrointestinal (GI) side effects and infections. RESULTS: A total of 1984 patients were included: 986 took leflunomide and 998 methotrexate. The probability of achieving ACR 20 had an odds ratio (OR) of 0.88 (95% confidence interval [CI] 0.74, 1.06) with a trend toward favoring methotrexate; reduction of the swollen joint count was greater for methotrexate: mean difference=0.82 (95%CI 0.24, 1.39); tender joint count, physician global assessment, HAQ-Di, and serum CRP levels revealed no significant difference between groups. Increased liver enzymes were more frequent in the leflunomide group, OR=0.38 (95%CI 0.27, 0.53), and new GI complaints were more common with methotrexate (OR=1.44; 95%CI 1.17, 1.79). There was no difference in the incidence of non-severe infections. CONCLUSION: Leflunomide used as the first DMARD in RA seemed to be as efficacious as methotrexate; only the reduction of swollen joint count was more marked for methotrexate. Leflunomide was linked to a greater increase in liver enzymes, but there were fewer GI complaints.

Rational Design of Microfabricated Electroconductive Hydrogels for Biomedical Applications.

Electroconductive hydrogels (ECHs) are highly hydrated 3D networks generated through the incorporation of conductive polymers, nanoparticles, and other conductive materials into polymeric hydrogels. ECHs combine several advantageous properties of inherently conductive materials with the highly tunable physical and biochemical properties of hydrogels. Recently, the development of biocompatible ECHs has been investigated for various biomedical applications, such as tissue engineering, drug delivery, biosensors, flexible electronics, and other implantable medical devices. Several methods for the synthesis of ECHs have been reported, which include the incorporation of electrically conductive materials such as gold and silver nanoparticles, graphene, and carbon nanotubes, as well as various conductive polymers (CPs), such as polyaniline, polypyrrole, and poly(3,4-ethylenedioxyythiophene) into hydrogel networks. Theses electroconductive composite hydrogels can be used as scaffolds with high swellability, tunable mechanical properties, and the capability to support cell growth both in vitro and in vivo. Furthermore, recent advancements in microfabrication techniques such as three dimensional (3D) bioprinting, micropatterning, and electrospinning have led to the development of ECHs with biomimetic microarchitectures that reproduce the characteristics of the native extracellular matrix (ECM). In addition, smart ECHs with controlled structures and healing properties have also been engineered into devices with prolonged half-lives and increased durability. The combination of sophisticated synthesis chemistries and modern microfabrication techniques have led to engineer smart ECHs with advanced architectures, geometries, and functionalities that are being increasingly used in drug delivery systems, biosensors, tissue engineering, and soft electronics. In this review, we will summarize different strategies to synthesize conductive biomaterials. We will also discuss the advanced microfabrication techniques used to fabricate ECHs with complex 3D architectures, as well as various biomedical applications of microfabricated ECHs.

Biomimetic cardiovascular platforms for in vitro disease modeling and therapeutic validation.

Bioengineered tissues have become increasingly more sophisticated owing to recent advancements in the fields of biomaterials, microfabrication, microfluidics, genetic engineering, and stem cell and developmental biology. In the coming years, the ability to engineer artificial constructs that accurately mimic the compositional, architectural, and functional properties of human tissues, will profoundly impact the therapeutic and diagnostic aspects of the healthcare industry. In this regard, bioengineered cardiac tissues are of particular importance due to the extremely limited ability of the myocardium to self-regenerate, as well as the remarkably high mortality associated with cardiovascular diseases worldwide. As novel microphysiological systems make the transition from bench to bedside, their implementation in high throughput drug screening, personalized diagnostics, disease modeling, and targeted therapy validation will bring forth a paradigm shift in the clinical management of cardiovascular diseases. Here, we will review the current state of the art in experimental in vitro platforms for next generation diagnostics and therapy validation. We will describe recent advancements in the development of smart biomaterials, biofabrication techniques, and stem cell engineering, aimed at recapitulating cardiovascular function at the tissue- and organ levels. In addition, integrative and multidisciplinary approaches to engineer biomimetic cardiovascular constructs with unprecedented human and clinical relevance will be discussed. We will comment on the implementation of these platforms in high throughput drug screening, in vitro disease modeling and therapy validation. Lastly, future perspectives will be provided on how these biomimetic platforms will aid in the transition towards patient centered diagnostics, and the development of personalized targeted therapeutics.

Interpenetrating network gelatin methacryloyl (GelMA) and pectin-g-PCL hydrogels with tunable properties for tissue engineering.

The design of new hydrogel-based biomaterials with tunable physical and biological properties is essential for the advancement of applications related to tissue engineering and regenerative medicine. For instance, interpenetrating polymer network (IPN) and semi-IPN hydrogels have been widely explored to engineer functional tissues due to their characteristic microstructural and mechanical properties. Here, we engineered IPN and semi-IPN hydrogels comprised of a tough pectin grafted polycaprolactone (pectin-g-PCL) component to provide mechanical stability, and a highly cytocompatible gelatin methacryloyl (GelMA) component to support cellular growth and proliferation. IPN hydrogels were formed by calcium ion (Ca2+)-crosslinking of pectin-g-PCL chains, followed by photocrosslinking of the GelMA precursor. Conversely, semi-IPN networks were formed by photocrosslinking of the pectin-g-PCL and GelMA mixture, in the absence of Ca2+ crosslinking. IPN and semi-IPN hydrogels synthesized with varying ratios of pectin-g-PCL to GelMA, with and without Ca2+-crosslinking, exhibited a broad range of mechanical properties. For semi-IPN hydrogels, the aggregation of microcrystalline cores led to formation of hydrogels with compressive moduli ranging from 3.1 to 10.4 kPa. For IPN hydrogels, the mechanistic optimization of pectin-g-PCL, GelMA, and Ca2+ concentrations resulted in hydrogels with comparatively higher compressive modulus, in the range of 39 kPa-5029 kPa. Our results also showed that IPN hydrogels were cytocompatible in vitro and could support the growth of three-dimensionally (3D) encapsulated MC3T3-E1 preosteoblasts in vitro. The simplicity, technical feasibility, low cost, tunable mechanical properties, and cytocompatibility of the engineered semi-IPN and IPN hydrogels highlight their potential for different tissue engineering and biomedical applications.

Photocrosslinkable Gelatin/Tropoelastin Hydrogel Adhesives for Peripheral Nerve Repair.

Suturing peripheral nerve transections is the predominant therapeutic strategy for nerve repair. However, the use of sutures leads to scar tissue formation, hinders nerve regeneration, and prevents functional recovery. Fibrin-based adhesives have been widely used for nerve reconstruction, but their limited adhesive and mechanical strength and inability to promote nerve regeneration hamper their utility as a stand-alone intervention. To overcome these challenges, we engineered composite hydrogels that are neurosupportive and possess strong tissue adhesion. These composites were synthesized by photocrosslinking two naturally derived polymers, gelatin-methacryloyl (GelMA) and methacryloyl-substituted tropoelastin (MeTro). The engineered materials exhibited tunable mechanical properties by varying the GelMA/MeTro ratio. In addition, GelMA/MeTro hydrogels exhibited 15-fold higher adhesive strength to nerve tissue ex vivo compared to fibrin control. Furthermore, the composites were shown to support Schwann cell (SC) viability and proliferation, as well as neurite extension and glial cell participation in vitro, which are essential cellular components for nerve regeneration. Finally, subcutaneously implanted GelMA/MeTro hydrogels exhibited slower degradation in vivo compared with pure GelMA, indicating its potential to support the growth of slowly regenerating nerves. Thus, GelMA/MeTro composites may be used as clinically relevant biomaterials to regenerate nerves and reduce the need for microsurgical suturing during nerve reconstruction.