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‐1β, 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.
RNAi delivery has great potential for the treatment of different diseases. However, there are multiple challenges such as intracellular delivery, stability, and toxicity when using RNAi therapy. To overcome these limitations, miRNAs are encapsulated in macrophage targeting nanoparticles and delivered locally to the wounds using an adhesive hydrogel. The adhesive seals the wound and promotes tissue healing in vivo.
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Electroconductive hydrogels (ECHs) are highly hydrated three-dimensional (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. These 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 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). 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.
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.
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.
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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.
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.
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.
Dental implants are the current solution for replacing of the missing teeth. However, majority of the patients with implants suffer from implant diseases caused by microbial infection and bone loss. There is an unmet need for the treatment of dental diseases. We developed a safe, cheap, and fast applicable glue with antimicrobial properties, designed for the treatment of periodontal diseases. This material can be delivered in liquid form around the implant and solidified by using a dental light to prevent infection and promote bone healing.
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.
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 (
=0.011). Left ventricular contractile function was better in GelMA-treated than untreated mice (fractional shortening 37% versus 26%,
<0.001). Average scar burden in GelMA-treated mice was lower than in untreated mice (6% versus 22%,
=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.
Conventional methods to engineer electroconductive hydrogels (ECHs) through the incorporation of conductive nanomaterials and polymers exhibit major technical limitations. These are mainly associated ...with the cytotoxicity, as well as poor solubility, processability, and biodegradability of their components. Here, we describe the engineering of a new class of ECHs through the functionalization of non-conductive polymers with a conductive choline-based bio-ionic liquid (Bio-IL). Bio-IL conjugated hydrogels exhibited a wide range of highly tunable physical properties, remarkable in vitro and in vivo biocompatibility, and high electrical conductivity without the need for additional conductive components. The engineered hydrogels could support the growth and function of primary cardiomyocytes in both two dimentinal (2D) and three dimensional (3D) cultures in vitro. Furthermore, they were shown to be efficiently biodegraded and possess low immunogenicity when implanted subcutaneously in rats. Taken together, our results suggest that Bio-IL conjugated hydrogels could be implemented and readily tailored to different biomedical and tissue engineering applications.
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