Implantable Hydrogels Research Articles

Smart Implantable Hydrogel for Large Segmental Bone Regeneration.

Large segmental bone defects often lead to nonunion and dysfunction, posing a significant challenge for clinicians. Inspired by the intrinsic bone defect repair logic of "vascularization and then osteogenesis", this study originally reports a smart implantable hydrogel (PDS-DC) with high mechanical properties, controllable scaffold degradation, and timing drug release that can proactively match different bone healing cycles to efficiently promote bone regeneration. The main scaffold of PDS-DC consists of polyacrylamide, polydopamine, and silk fibroin, which endows it with superior interfacial adhesion, structural toughness, and mechanical stiffness. In particular, the adjustment of scaffold cross-linking agent mixing ratio can effectively regulate the in vivo degradation rate of PDS-DC and intelligently satisfy the requirements of different bone defect healing cycles. Ultimately, PDS hydrogel loaded with free desferrioxamine (DFO) and CaCO3 mineralized ZIF-90 loaded bone morphogenetic protein-2 (BMP-2) to stimulate efficient angiogenesis and osteogenesis. Notably, DFO is released rapidly by free diffusion, whereas BMP-2 is released slowly by pH-dependent layer-by-layer disintegration, resulting in a significant difference in release time, thus matching the intrinsic logic of bone defect repair. In vivo and in vitro results confirm that PDS-DC can effectively realize high-quality bone generation and intelligently regulate to adapt to different demands of bone defects.

Hydrogels in the clinic: An update.

Hydrogels have been used in the clinic since the late 1980s with broad applications in drug delivery, cosmetics, tissue regeneration, among many other areas. The past three decades have witnessed rapid advances in the fields of polymer chemistry, crosslinking approaches, and hydrogel fabrication methods, which have collectively brought many new hydrogel products, either injectable or non-injectable, to clinical studies. In an article published in 2020 entitled "Hydrogels in the clinic", we reviewed the clinical landscape and translational challenges of injectable hydrogels. Here, we provide an update on the advances in the field and also extend the scope to include non-injectable hydrogels. We highlight recently approved hydrogel products, provide an update on the clinical trials of injectable hydrogels, and discuss active clinical trials of topically applied and implantable hydrogels.

3D Printed Implantable Hydrogel Bioelectronics for Electrophysiological Monitoring and Electrical Modulation (Adv. Funct. Mater. 21/2024)

3D Printed Implantable Hydrogel Bioelectronics for Electrophysiological Monitoring and Electrical Modulation (Adv. Funct. Mater. 21/2024)

Nonwoven Reinforced Photocurable Poly(glycerol sebacate)-Based Hydrogels.

Implantable hydrogels should ideally possess mechanical properties matched to the surrounding tissues to enable adequate mechanical function while regeneration occurs. This can be challenging, especially when degradable systems with a high water content and hydrolysable chemical bonds are required in anatomical sites under constant mechanical stimulation, e.g., a foot ulcer cavity. In these circumstances, the design of hydrogel composites is a promising strategy for providing controlled structural features and macroscopic properties over time. To explore this strategy, the synthesis of a new photocurable elastomeric polymer, poly(glycerol-co-sebacic acid-co-lactic acid-co-polyethylene glycol) acrylate (PGSLPA), is investigated, along with its processing into UV-cured hydrogels, electrospun nonwovens and fibre-reinforced variants, without the need for a high temperature curing step or the use of hazardous solvents. The mechanical properties of bioresorbable PGSLPA hydrogels were studied with and without electrospun nonwoven reinforcement and with varied layered configurations, aiming to determine the effects of the microstructure on the bulk compressive strength and elasticity. The nonwoven reinforced PGSLPA hydrogels exhibited a 60% increase in compressive strength and an 80% increase in elastic moduli compared to the fibre-free PGSLPA samples. The mechanical properties of the fibre-reinforced hydrogels could also be modulated by altering the layering arrangement of the nonwoven and hydrogel phase. The nanofibre-reinforced PGSLPA hydrogels also exhibited good elastic recovery, as evidenced by the hysteresis in compression fatigue stress-strain evaluations showing a return to the original dimensions.

Slippery Core‐Sheath Hydrogel Optical Fiber Built by Catalytically Triggered Interface Radical Polymerization

AbstractHydrogel‐based optical waveguides have attracted extensive attention in optogenetics, implantable photomedicine, and biosensors due to their excellent biocompatibility and tissue‐like modulus in compared with traditional SiO2‐based rigid optical fibers. However, the existing ion‐induced supramolecular assembly of alginate‐based hydrogel optical fibers commonly lack of long‐term stability due to poor mechanical property accompanied with swollen. In this paper, a novel catalytic surface polymerization method is developed based on a redox reaction mechanism to in situ grow robust and slippery cladding layer on a core poly(ethylene glycol) dimethacrylate (PEGDA) hydrogel fiber by using the alternative H‐bonding poly(N ‐acryloyl glycinamide) (PNAGA) hydrogels. The resultant hydrogel optical fiber with core‐cladding heterogeneous structure can achieve the desirable total reflection condition, leading to good light transmission and low light loss. The PNAGA cladding with robust H‐bonding network endows the hydrogel optical fiber with high stability and outstanding lubrication in humid environment. More importantly, the hydrogel optical fiber possesses good tissue‐like mechanical performance together with excellent biocompatibility, which shows the great advantages for biomedical applications in compared with traditional glass optical fibers. This work will broaden implantable hydrogel optical fibers in material design and structure processibility, promoting the use of hydrogel‐based optical fibers in various applications.

Hydrogel Based on Riclin Cross-Linked with Polyethylene Glycol Diglycidyl Ether as a Soft Filler for Tissue Engineering.

Hydrogels composed of natural polysaccharides have been widely used as filling materials, with a growing interest in medical cosmetology and skin care. However, conventional commercial dermal fillers still have limitations, particularly in terms of mechanical performance and durability in vivo. In this study, a novel injectable and implantable hydrogel with adjustable characteristics was prepared from succinoglycan riclin by introducing PEG diglycidyl ether as a cross-linker. FTIR spectra confirmed the cross-linking reaction. The riclin hydrogels exhibited shear-thinning behavior, excellent mechanical properties, and cytocompatibility through in vitro experiments. Furthermore, when compared with subcutaneous injection of a commercial hyaluronic acid hydrogel, the riclin hydrogels showed enhanced persistence and biocompatibility in Balb/c mice after 16 weeks. These results demonstrate the great potential of the riclin-based hydrogel as an alternative to conventional commercial soft tissue fillers.

Ultrasensitive Optical Detection and Elimination of Residual Microtumors with a Postoperative Implantable Hydrogel Sensor for Preventing Cancer Recurrence.

In vivo optical imaging of trace biomarkers in residual microtumors holds significant promise for cancer prognosis but poses a formidable challenge. Here, a novel hydrogel sensor is designed for ultrasensitive and specific imaging of the elusive biomarker. This hydrogel sensor seamlessly integrates a molecular beacon nanoprobe with fibroblasts, offering both high tissue retention capability and an impressive signal-to-noise ratio for imaging. Signal amplification is accomplished through exonuclease I-mediated biomarker recycling. The resulting hydrogel sensor sensitively detects the biomarker carcinoembryonic antigen with a detection limit of 1.8pgmL-1 in test tubes. Moreover, it successfully identifies residual cancer nodules with a median diameter of less than 2mm in mice bearing partially removed primary triple-negative breast carcinomas (4T1). Notably, this hydrogel sensor is proven effective for the sensitive diagnosis of invasive tumors in post-surgical mice with infiltrating 4T1 cells, leveraging the role of fibroblasts in locally enriching tumor cells. Furthermore, the residual microtumor is rapidly photothermal ablation by polydopamine-based nanoprobe under the guidance of visualization, achieving ≈100% suppression of tumor recurrence and lung metastasis. This work offers a promising alternative strategy for visually detecting residual microtumors, potentially enhancing the prognosis of cancer patients following surgical interventions.

3D Printed Implantable Hydrogel Bioelectronics for Electrophysiological Monitoring and Electrical Modulation

AbstractElectronic devices based on conducting polymer hydrogels have emerged as one of the most promising implantable bioelectronics for electrophysiological monitoring and diagnosis of a wide spectrum of diseases, in light of their distinct conductivity and biocompatibility. However, most conducting polymer hydrogels‐based bioelectronics are routinely fabricated through conventional techniques, which are challenged by its intrinsic poor processability of conducting polymers, as well as the essentially fragile biointerface, thus hampering their rapid innovation and application in advanced implantable bioelectronics. Here, 3D printable hydrogels based on poly(3,4‐ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS) is reported, featuring superior 3D printability for direct ink writing (DIW), tissue‐like mechanical compliance (Young's modulus of 650 kPa), instant and tough bioadhesion (interfacial toughness of 200 J m−2 and shear strength of 120 kPa), highly‐tunable electrical properties, as well as long‐term in vitro and in vivo structural and electrochemical robustness. Electro‐physiological studies rat heart models with normal or arrhythmic conditions highlight the capabilities of establishing conformal biointerface with the dynamic organs, allowing for long‐term and high‐precision spatiotemporary epicardial electrophysiological monitoring, as well as electrical modulation of acute myocardial infarction (MI) model. These advances provide a promising strategy to improve the tissue‐electronics interfacing, and could serve as the basis for the next generation bioelectronics toward healthcare monitoring, diagnosis and medical therapies.

Non-contact monitoring of glucose concentration and pH by integration of wearable and implantable hydrogel sensors with optical coherence tomography.

Optical coherence tomography (OCT) is a noninvasive imaging technique with large penetration depth into the tissue, but limited chemical specificity. By incorporating functional co-monomers, hydrogels can be designed to respond to specific molecules and undergo reversible volume changes. In this study, we present implantable and wearable biocompatible hydrogel sensors combined with OCT to monitor their thickness change as a tool for continuous and real-time monitoring of glucose concentration and pH. The results demonstrate the potential of combining hydrogel biosensors with OCT for non-contact continuous in-vivo monitoring of physiological parameters.

Prospective applications of hydrogels for the intra-articular treatment of osteoarthritis

Introduction Osteoarthritis (OA) is a degenerative disease that leads to gradual loss of cartilage and the formation of osteophytes, and consequently to joint instability, pain, and limited mobility. Treatment options include drug therapy, physiotherapy, lifestyle changes and surgery to correct or replace the joint. Intra-articular treatments, such as the injection of hydrogels modified for specific clinical tasks, are becoming increasingly popular due to their ability to provide targeted and effective relief with minimal side effects.Purpose of this study was to evaluate the use of hydrogels for the intra-articular treatment of osteoarthritis (OA) based on a review of scientific literature.Materials and methods Literature sources for the evaluation of the use of hydrogels for the intraarticular treatment of OA were selected using the subject search queries “hydrogel” AND “intra? articular” AND “osteoarthritis” in the PubMed, ScienceDirect and SciSpace databases. The search period was limited to 2018–2023 years of publication. An initial selection of articles by search glories resulted in 1,576 articles; after analysis and application of exclusion criteria, 53 of the most relevant sources were included in the review.Results Two types of hydrogels for intra-articular use have been dentified: injectable and implantable. Injectable hydrogels are used to replace synovial fluid, deliver drugs or fill focal cartilage defects. Implantable hydrogels are used to replace or repair damaged cartilage in joints affected by OA, thereby restoring surface integrity, reducing pain and improving function.Discussion Hydrogels demonstrate promise as a potential material for the treatment of OA as they offer several advantages, such as biomimicry, biocompatibility, minimally invasive administration and the ability to deliver therapeutic agents directly to the affected joint. However, there are limitations: uncontrolled degradation, low durability and a high likelihood of negative local and systemic immune reactions.Conclusion Further research is needed to optimize the design and composition of hydrogels for clinical use, including the development of new compositions with programmable properties, studying long-term effects and comparing effectiveness with other OA treatment.

Hydrogels with Phosphate Groups as Potential Carriers of Bisphosphonates

Hydrogels are potential materials in many biomedical applications. A particularly promising application is their use in bone tissue engineering as implants or layers on the surface of titanium alloys. Disadvantage in the use of hydrogels in drug release system is often “burst release” effect what obstructs controlled release of pharmaceutically active agent. This functionality can be obtained by using an appropriate hydrogel, which has in its structure ions to which the drug is complexed. In this work, hydrogel materials containing mers with phosphate groups were prepared and used in the controlled drug release. The prepared material was functionalized with Ca2+, Mg2+, and Sr2+ ions. These ions were chosen because they support the osseointegration process. The possibility of sorption of the drug for osteoporosis (risedronate) was tested on the prepared hydrogels. Sorption was effective only on the hydrogel with calcium ions. The drug was evenly distributed throughout the hydrogel. The new hydrogel has proven to be able to retain the drug and slowly release it in small doses. We assume that the prepared material has the potential to be used as a coating for bone implants or as an implantable hydrogel for people suffering from osteoporosis.

A Core-Shell Nanoreinforced Ion-Conductive Implantable Hydrogel Bioelectronic Patch with High Sensitivity and Bioactivity for Real-Time Synchronous Heart Monitoring and Repairing.

To achieve synchronous repair and real-time monitoring the infarcted myocardium based on an integrated ion-conductive hydrogel patch is challenging yet intriguing. Herein, a novel synthetic strategy is reported based on core-shell-structured curcumin-nanocomposite-reinforced ion-conductive hydrogel for synchronous heart electrophysiological signal monitoring and infarcted heart repair. The nanoreinforcement and multisite cross-linking of bioactive curcumin nanoparticles enable well elasticity with negligible hysteresis, implantability, ultrahigh mechanoelectrical sensitivity (37ms), and reliable sensing capacity (over 3000 cycles) for the nanoreinforced hydrogel. Results of in vitro and in vivo experiments demonstrate that such solely physical microenvironment of electrophysiological and biomechanical characteristics combining with the role of bioactive curcumin exert the synchronous benefit of regulating inflammatory microenvironment, promoting angiogenesis, and reducing myocardial fibrosis for effective myocardial infarction (MI) repair. Especially, the hydrogel sensors offer the access for achieving accurate acquisition of cardiac signals, thus monitoring the whole MI healing process. This novel bioactive and electrophysiological-sensing ion-conductive hydrogel cardiac patch highlights a versatile strategy promising for synchronous integration of in vivo real-time monitoring the MI status and excellent MI repair performance.

Minimally-Invasive and In-Vivo Hydrogel Patterning Method for In Situ Fabrication of Implantable Hydrogel Devices.

Despite advances in a wide range of device applications of hydrogels, including implantable ones, a method for deploying patterned hydrogel devices into the body in a minimally-invasive manner is not available yet. However, in situ patterning of the hydrogel in vivo has an obvious advantage, by which incision surgery for implantation of the hydrogel device can be avoided. Here, a minimally-invasive and in vivo hydrogel patterning method for in situ fabrication of implantable hydrogel devices is presented. The sequential application of injectable hydrogels and enzymes, with assistance of minimally-invasive surgical instruments, enables the in vivo and in situ hydrogel patterning. This patterning method can be achieved by adopting an appropriate combination of the sacrificial mold hydrogel and the frame hydrogel, in consideration of unique material properties of the hydrogels such as high softness, facile mass transfer, biocompatibility, and diverse crosslinking mechanisms. In vivo and in situ patterning of the hydrogels functionalized with nanomaterials is also demonstrated to fabricate the wireless heater and tissue scaffold, showcasing broad applicability of the patterning method.

Chitosan hydrogel modified with lanthanum as a drug delivery system for epigallocatechin gallate: Investigation of hydrogel – drug interaction by FT-IR and Raman spectroscopy

In the presented work, chitosan hydrogel modified with lanthanum was obtained for the first time. The hydrogel was used as a carrier in the controlled release of epigallocatechin gallate. The work proved the effectiveness of drug sorption by hydrogel and controlled release in simulated body fluids. The drug was released slowly and in a controlled manner from the carrier. The research techniques used in this work (FT-IR spectroscopy and imaging, Raman spectroscopy, SEM/EDS) allowed to confirm the successful retention of EGCG on the hydrogel surface. On the basis of the EDS mapping, it was possible to confirm the even distribution of the lanthanum ions. Using FT-IR imaging, we verified that the drug was evenly distributed on the entire surface of the prepared material. The antifungal effectiveness of the material has been proven on several types of fungi. The research proved that the prepared material is capable of long-term release of the active substance and has antifungal properties. As a result, the prepared material can be successfully used as an implantable hydrogel or a coating in, e.g. titanium implants.

Chitosan modified with lanthanum ions as implantable hydrogel for local delivery of bisphosphonates

Osteoporosis is a disease that affects many people around the world. One group of drugs used to treat it are bisphosphonates. However, they have poor bioavailability and many side effects. Therefore, research around the world is focused on developing bisphosphonate delivery systems. In this paper, we would like to present the design of a hydrogel material with chitosan matrix modified with lanthanum, that could serve as an implantable hydrogel capable of sustained and slow release of Zoledronate. Various research techniques were used to characterize the materials, and the swelling ratio and water solubility were also tested. The conducted research proved that the prepared hydrogel is capable of the long-term release of the Zoledronate. Thanks to this, the prepared material can be successfully used as an implantable hydrogel or a coating on titanium implants for the local delivery of drugs.

Ultrasound Responsive Smart Implantable Hydrogels for Targeted Delivery of Drugs: Reviewing Current Practices.

Over the last two decades, the process of delivering therapeutic drugs to a patient with a controlled release profile has been a significant focus of drug delivery research. Scientists have given tremendous attention to ultrasound-responsive hydrogels for several decades. These smart nanosystems are more applicable than other stimuli-responsive drug delivery vehicles (ie UV-, pH- and thermal-, responsive materials) because they enable more efficient targeted treatment via relatively non-invasive means. Ultrasound (US) is capable of safely transporting energy through opaque and complex media with minimal loss of energy. It is capable of being localized to smaller regions and coupled to systems operating at various time scales. However, the properties enabling the US to propagate effectively in materials also make it very difficult to transform acoustic energy into other forms that may be used. Recent research from a variety of domains has attempted to deal with this issue, proving that ultrasonic effects can be used to control chemical and physical systems with remarkable specificity. By obviating the need for multiple intravenous injections, implantable US responsive hydrogel systems can enhance the quality of life for patients who undergo treatment with a varied dosage regimen. Ideally, the ease of self-dosing in these systems would lead to increased patient compliance with a particular therapy as well. However, excessive literature has been reported based on implanted US responsive hydrogel in various fields, but there is no comprehensive review article showing the strategies to control drug delivery profile. So, this review was aimed at discussing the current strategies for controlling and targeting drug delivery profiles using implantable hydrogel systems.

Recent advances in implantable hydrogels for treating heart failure

AbstractHeart failure (HF) is an irreversible disease characterized by the reducing capacity of blood supply as a consequence of cardiomyocyte death and deteriorated fibrosis. There is a lack of effective treatment for heart failure other than a heart transplant, and thus significant resources have been dedicated to developing functional materials for cardiac tissue engineering. Implanting hydrogels in the myocardium near the myocardial infarction area can preserve cardiac function and slow the remodeling that leads to HF by providing mechanical support to the ventricular wall. Nevertheless, few reviews have been published for this promising HF treatment. Herein, we briefly discuss the classification and existing conventional treatments for HF and provide an overview of recent functional hydrogels designed for cardiac repair after myocardial infarction, including polymeric hydrogels, polymer‐cell complex hydrogels, polymer‐cytokine complex hydrogels, and polymer‐protein complex hydrogels. Key challenges and future directions for advanced hydrogels have also been discussed.

Biodegradable gellan gum hydrogels loaded with paclitaxel for HER2+ breast cancer local therapy

Hydrogels loaded with chemotherapeutics are promising tools for local tumor treatment. In this work, redox-responsive implantable hydrogels based on gellan gum were prepared as paclitaxel carriers for HER2-positive breast cancer therapy. To achieve different degrees of chemical crosslinking, hydrogels were synthesized in both acetate buffer and phosphate buffer and crosslinked with different concentrations of l-cysteine. It was shown that both, the type of buffer and the l-cysteine concentration used, conditioned the dynamic modulus, equilibrium swelling rate, porosity, and thermal stability of the hydrogels. Then, the biocompatibility of the hydrogels with the most suitable porosity for drug delivery applications was assessed. Once confirmed, these hydrogels were loaded with paclitaxel:β-cyclodextrin inclusion complexes, and they showed a glutathione-responsive controlled release of the taxane. Moreover, when tested in vitro, paclitaxel-loaded hydrogels exhibited great antitumor activity. Thus, they could act as excellent local tailored carriers of paclitaxel for future, post-surgical treatment of HER2-overexpressing breast tumors.

Sugar-Assisted Cryopreservation of Stem Cell-Laden Gellan Gum-Collagen Interpenetrating Network Hydrogels.

Tissue engineering involves the transplantation of stem cell-laden hydrogels as synthetic constructs to replace damaged tissues. However, their time-consuming fabrication procedures are hurdles to widespread application in clinics. Fortunately, similar to cell banking, synthetic tissues could be cryopreserved for subsequent central distribution. Here, we report the use of trehalose and gellan gum as biomacromolecules to form a cryopreservable yet directly implantable hydrogel system for adipose-derived stem cell (ADSC) delivery. Through a modified cell encapsulation method and a preincubation step, adequate cryoprotection was afforded at 0.75 M trehalose to the encapsulated ADSCs. At this concentration, trehalose demonstrated lower propensity to induce apoptosis than 10% DMSO, the current gold standard cryoprotectant. Moreover, when cultured along with trehalose after thawing, the encapsulated ADSCs retained their stem cell-like phenotype and osteogenic differentiation capacity. Taken together, this study demonstrates the feasibility of an “off-the-shelf” biomacromolecule-based synthetic tissue to be applied in widespread tissue engineering applications.

Standardised quantitative ultrasound imaging approach for the contact-less three-dimensional analysis of neocartilage formation in hydrogel-based bioscaffolds

In this work we present a standardised quantitative ultrasound imaging (SQUI) approach for the non-destructive three-dimensional imaging and quantification of cartilage formation in hydrogel based bioscaffolds. The standardised concept involves the processing of ultrasound backscatter data with respect to an acellular phantom in combination with the compensation of sound speed mismatch diffraction effects between the bioscaffold and the phantom. As a proof-of-concept, the SQUI approach was tested on a variety of bioscaffolds with varying degree of neocartilage formation. These were composed of Gelatine Methacryloyl (GelMA) hydrogels laden with human adipose-derived stem cells (hADSCs). These were cultured under chondrogenic stimulation following a previously established protocol, where the degree of the neocartilage formation was modulated using different GelMA network densities (6, 8, 10 % w/v) and culture time (0, 14, 28 days). Using the SQUI approach we were able to detect marked acoustic and morphological changes occurring in the bioscaffolds a result of their different chondrogenic outcome. We defined an acoustic neocartilage indicator, the sonomarker, for the selective imaging and quantification of neocartilage formation. The sonomarker, of backscatter intensity logIBC -2.4, was found to correlate with data obtained via standard destructive bioassays. The ultrasonic evaluation of human specimens confirmed the sonomarker as a relevant intensity, although it was found to shift to higher intensity values in proportion to the cartilage condition as inferred from sound speed measurements. This study demonstrates the potential of the SQUI approach for the realization of non-destructive analysis of cartilage regeneration over-time. Statement of significanceAs tissue engineering strategies for neocartilage regeneration evolve towards clinical implementation, alternative characterisation approaches that allow the non-destructive monitoring of extracellular matrix formation in implantable hydrogel based bioscaffolds are needed. In this work we present an innovative standardized quantitative ultrasound imaging (SQUI) approach that allows the non-destructive, volumetric, and quantitative evaluation of neocartilage formation in hydrogel based bioscaffolds. The standardised concept aims to provide a robust approach that accounts for the dynamic changes occurring during the conversion from a cellular bioscaffold towards the formation of a neocartilage construct. We believe that the SQUI approach will be of great benefit for the evaluation of constructs developing neocartilage, not only for in-vitro applications but also potentially applicable to in-vivo applications.