Inspired by how forces facilitate molecule immobilization in biological tissues to provide localized functionalization, tough hydrogel networks with stretch activated mechanochemistry are developed by utilizing disulfide bonds as dynamic covalent crosslinks. Specifically, disulfide linked polyethylene glycol hydrogels are reinforced with a second ionically bonded sodium alginate network to simultaneously achieve stretchability and mechanochemical functionalization. To demonstrate and quantify the mechanochemical response, thiols produced by disulfide bond rupture are sensed during stretching using a reaction activated fluorophore dissolved in the hydrating solution. By monitoring the increase in fluorescence intensity upon stretching, it is determined that disulfide bond breakage in the double network hydrogels becomes more activated in hydrogels with high stretchability under low stress. Such results provide guidance regarding how the molecular weights and mass fractions of the monomers must be chosen to design double network hydrogels that balance favorable mechanical properties and mechanochemical responsiveness. Finally, for the most mechanochemically active hydrogel, we demonstrate how the stretch-activated immobilization of a maleimide containing peptide can functionalize the gels to promote the growth of human fibroblasts. Results of this work are anticipated to encourage further research into the development of stretchable and multifunctionalizable hydrogels for biotechnology and biomedical applications. STATEMENT OF SIGNIFICANCE: Inspired by the mechanochemical dynamics in biological tissues, this work demonstrates the development of hydrogel-based biomaterials that can achieve stretch activated functionalization by molecule immobilization in multiple distinct ways. Using disulfide linked polyethylene glycol hydrogels reinforced with a second alginate network, we have elucidated the structure-property relationships of our hydrogels by functionalizing them with fluorophore to ensure a robust combination of stretchability and mechanochemical responsiveness. We also have demonstrated the capability for using stretch activated immobilization of functional peptides to guide human fibroblasts activity. By demonstrating how hydrogel network properties impact both mechanical and functional performance, this work opens pathways for designing multifunctionalizable hydrogels that adapt to mechanical forces, potentially broadening the application of hydrogels in biotechnology and biomedical applications.

Significance: Volumetric muscle loss is defined as composite loss of muscle mass. Severe injuries result in permanent functional impairment. Treatment options are limited. Tissue engineering techniques utilizing scaffolds offer promise as a potential therapy. Recent Advances: Emerging strategies, including bioactive molecules and growth factors in biocompatible scaffolds, may promote muscle regeneration following severe injury. In this context, scaffolds can act as a drug-delivery device, provide guidance to cells as a supporting matrix, and slowly release growth factors to promote healing. Critical Issues: Scaffolds engraftment and ability to promote tissue regeneration in injured beds remain limited. Tuning and optimizing scaffold fiber diameter, alignment, cellular cues, growth factor delivery, and porosity will be important in reconstituting functional skeletal muscle following loss. Future Directions: Our mechanistic understanding of interactions between biomimetic scaffolds and host tissue is still evolving, and future research can identify factors to promote tissue regeneration.

Chronic wounds present significant clinical challenges due to delayed healing and high infection risk. This study presents the development and characterisation of acrylated hyaluronic acid (AcHyA) hydrogels functionalised with gelatin (G) and the antimicrobial peptide (AMP) PP4-3.1 to enhance cellular responses while providing antimicrobial activity. AcHyA-G and AcHyA-AMP hydrogels were formed via thiol-acrylate crosslinking, enabling in situ AcHyA hydrogel formation with stable mechanical properties across varying gelatin concentrations. Biophysical characterisation of AcHyA-G hydrogels showed rapid gelation, elastic behaviour, uniform mesh size, and consistent molecular diffusion across all formulations. Moreover, the presence of gelatin enhanced stability without affecting the hydrogel's degradation kinetics. AcHyA-G hydrogels supported the adhesion and spreading of key cell types involved in wound repair (dermal fibroblasts and endothelial cells), with 0.5% gelatin identified as the optimal effective concentration. Furthermore, the conjugation of the AMP conferred bactericidal activity against Staphylococcus aureus and Escherichia coli, two of the most prevalent bacterial species found in chronically infected wounds. These results highlight the dual function of AcHyA-AMP hydrogels in promoting cellular responses and antimicrobial activity, offering a promising strategy for chronic wound treatment. Further in vivo studies are needed to evaluate their efficacy, including in diabetic foot ulcers.

Insufficient bone volume is a major problem in implant dentistry, which can be counteracted by using guided bone regeneration technique. Among the materials recently tested, synthetic polymers have been recommended as showing excellent biocompatibility and biodegradability.

The aim of this pilot study was to analyze and compare through means of histology the healing of the bone tissue in critical size osseous defects in New-Zealand rabbit tibiae after application of beta-tricalcium phosphate (β-TCP) alone, β-TCP combined with leucocyte platelet-rich fibrin (L-PRF) and an injectable experimental bone cement (EBC) represented by a dual-curable degradable synthetic polymer.

Two New-Zealand rabbits were used. Three standardized osseous defects of 5 mm diameter were created in each tibia. Each defect was filled with either β-TCP alone (control), β-TCP combined with L-PRF (test) or with EBC (test). The animals were sacrificed at 25 and 70 days; the tibia samples were removed, fixed in 10 % formaldehyde and stained with AZAN.

While at 25 days β-TCP produced sparse bone formation, at 70 days mature bone formation was visible in all areas of the defect with minimum remaining graft particles; at 25 days, β-TCP combined with L-PRF produced broad areas of bone lamellae, while at 70 days bone tissue formation was limited; at both 25 and 70 days, the EBC was stable and not penetrated by bone cells, while a narrow band of connective tissue could be seen superjacent and inferior to it.

Among the tested biomaterials, β-TCP was capable of generating bone formation at both healing time-points, while the addition of L-PRF seemed to provide a synergistic effect only in the early phase of bone healing.

Brain organoids are an emerging in vitro 3D brain model that is integrated from pluripotent stem cells. This model mimics the human brain's developmental process and disease-related phenotypes to a certain extent while advancing the development of human brain-based biological intelligence. However, many limitations of brain organoid culture (e.g., lacking a functional vascular system, etc.) prevent in vitro-cultured organoids from truly replicating the human brain in terms of cell type and structure. To improve brain organoids' scalability, efficiency, and stability, this paper discusses important contributions of material biology and microprocessing technology in solving the related limitations of brain organoids and applying the latest imaging technology to make real-time imaging of brain organoids possible. In addition, the related applications of brain organoids, especially the development of organoid intelligence combined with artificial intelligence, are analyzed, which will help accelerate the rational design and guidance of brain organoids.

Intervertebral disc degeneration (IDD) arises from a complex interplay of genetic, environmental, and age-related factors, culminating in a spectrum of low back pain (LBP) disorders that exert significant societal and economic impact. The present therapeutic landscape for IDD poses formidable clinical hurdles, necessitating the exploration of innovative treatment modalities. The hydrogel, as a biomaterial, exhibits superior biocompatibility compared to other biomaterials such as bioceramics and bio-metal materials. It also demonstrates mechanical properties closer to those of natural intervertebral discs (IVDs) and favorable biodegradability conducive to IVD regeneration. Therefore, it has emerged as a promising candidate material in the field of regenerative medicine and tissue engineering for treating IDD. Hydrogels have made significant strides in the field of IDD treatment. Particularly, injectable hydrogels not only provide mechanical support but also enable controlled release of bioactive molecules, playing a crucial role in mitigating inflammation and promoting extracellular matrix (ECM) regeneration. Furthermore, the ability of injectable hydrogels to achieve minimally invasive implantation helps minimize tissue damage. This article initially provides a concise exposition of the structure and function of IVD, the progression of IDD, and delineates extant clinical interventions for IDD. Subsequently, it categorizes hydrogels, encapsulates recent advancements in biomaterials and cellular therapies, and delves into the mechanisms through which hydrogels foster disc regeneration. Ultimately, the article deliberates on the prospects and challenges attendant to hydrogel therapy for IDD.

Tumor organoid models have emerged as valuable 3D in vitro systems to study cancer behavior in a physiologically relevant environment. The composition and architecture of the extracellular matrix (ECM) play critical roles in tumor organoid culture by influencing the tumor microenvironment and tumor behavior. Traditional matrices such as Matrigel and collagen, have been widely used, but their batch-to-batch variability and limited tunability hinder their reproducibility and broader applications. To address these challenges, researchers have turned to synthetic/engineered matrices and biopolymer-based matrices, which offer precise tunability, reproducibility, and chemically defined compositions. However, these matrices also present challenges of their own. In this review, we explore the significance of ECMs in tumor organoid culture, discuss the limitations of commonly used matrices, and highlight recent advancements in engineered/synthetic matrices for improved tumor organoid modeling.

Chronic inflammation at bone defect sites can impede regenerative processes, but local immune responses can be adjusted to promote healing. Regulating the osteoimmune microenvironment, particularly through macrophage polarization, has become a key focus in bone regeneration research. While bone implants are crucial for addressing significant bone defects, they are often recognized by the immune system as foreign, triggering inflammation that leads to bone resorption and implant issues like fibrous encapsulation and aseptic loosening. Developing osteoimmunomodulatory implants offers a promising approach to transforming destructive inflammation into healing processes, enhancing implant integration and bone regeneration. This review explores strategies based on tuning the physicochemical attributes and chemical composition of materials in engineering osteoimmunomodulatory and pro-regenerative bone implants.

Heart failure (HF) affects over 64 million people globally, marked by high incidence and mortality rates. Accurate measurements of myocardial contractility are crucial for evaluating cardiac pathomechanisms and monitoring disease progression. Hydrogel sensing devices, known for their flexibility, programmable structures, biocompatibility, and cell adhesion, are ideal for studying cardiac function, minimizing disruption to cardiomyocytes, and supporting long-term culture and monitoring. These platforms, while employing diverse detection principles to accurately measure cell contractility, still face challenges in achieving long-term stability and durability. This review summarizes current methods for monitoring cardiomyocyte contractility, emphasizes the significant impact of substrate mechanical properties on cellular function, and explores recent advances in hydrogel-based platforms for monitoring cell contraction forces. It also discusses the technical challenges and future prospects for measuring cardiac systolic function with these devices.

Cardiovascular disease remains the leading cause of global mortality. Current stem cell therapy and heart transplant therapy have limited long-term stability in cardiac function. Cardiac tissue engineering may be one of the key methods for regenerating damaged myocardial tissue. As an ideal scaffold material, hydrogel has become a viable tissue engineering therapy for the heart. Hydrogel can not only provide mechanical support for infarcted myocardium but also serve as a carrier for various drugs, bioactive factors, and cells to increase myocardial contractility and improve the cell microenvironment in the infarcted area, thereby improving cardiac function. This paper reviews the applications of hydrogels and biomedical mechanisms in cardiac tissue engineering and discusses the challenge of clinical transformation of hydrogel in cardiac tissue engineering, providing new strategies for treating cardiovascular diseases.

A common strategy for promoting bone allograft healing is the design of tissue-engineered periosteum (TEP) to orchestrate host-tissue infiltration. However, evaluating requires costly and time-consuming in vivo studies. Therefore, in vitro assays are necessary to expedite TEP designs. Since angiogenesis is a critical process orchestrated by the periosteum, this study investigates in vitro 3D cell spheroid vascularization as a predictive tool for TEP-mediated in vivo healing. Spheroids of human umbilical vein endothelial cells (HUVECs) and human mesenchymal stem cells (hMSCs) are encapsulated in enzymatically-degradable poly (ethylene glycol)-based hydrogels and sprout formation, network formation, and angiogenic growth factor secretion are quantified. Hydrogels are also evaluated as TEP-modified allografts for in vivo bone healing with graft vascularization, callus formation, and biomechanical strength quantified as healing metrics. Evaluation of hydrogels highlights the importance of degradation, with 24-fold greater day 1 sprouts observed in degradable hydrogels in vitro and 4-fold greater graft-localized vascular volume at 6-weeks in vivo compared to non-degradable hydrogels. Correlations between in vitro and in vivo studies elucidate linear relationships when comparing in vitro sprout formation and angiocrine production with 3- and 6-week in vivo graft vascularization, 3-week cartilage callus, and 6-week bone callus, with a Pearson's R2 value equal to 0.97 for the linear correlation between in vitro sprout formation and 6-week in vivo vascular volume. Non-linear relationships are found between in vitro measures and bone torque strength at week 6. These correlations suggest that the in vitro sprouting assay has predictive power for in vivo vascularization and bone allograft healing.

Liver fibrosis (LF) is an important process in the progression of chronic liver disease to cirrhosis. We have previously demonstrated that a regenerated silk fibroin scaffold loaded with adipose-derived stem cells (RSF + ADSCs) can repair acute liver injury. In this study, we established a chronic LF animal model using carbon tetrachloride (CCl4) and a high-fat diet. We then investigated the liver repair capacity after transplanting RSF + ADSC scaffolds and RSF scaffolds onto the liver surface of mice. Compared with the control group, the concentrations of ALT and AST in the serum were significantly reduced in the RSF and RSF + ADSC groups. HE staining and Masson trichrome staining revealed a decrease in the SAF score in both the RSF and RSF + ADSC groups. Meanwhile, the biomarkers of blood vessels and bile ducts, such as CD34, ERG, muc1, and CK19, were significantly elevated in the RSF + ADSC group. Finally, transcriptome analysis showed that the PPAR signaling pathway, which inhibits liver fibrosis, was significantly upregulated in both the RSF and RSF + ADSC groups. Our study suggests that, compared with RSF scaffolds alone, RSF + ADSCs have a significant repair effect on chronic LF in mice.

The extracellular matrix (ECM) is a dynamic network providing mechanical and biochemical cues that regulate cellular behavior. ECM stiffness critically influences fibroblasts, the primary ECM producers, particularly in inflammation and fibrosis. This review explores the role of ECM stiffness in fibroblast-driven inflammation and tissue remodeling, focusing on the physicochemical and biological mechanisms involved. Engineered materials, hydrogels, and polydimethylsiloxane (PDMS) are highlighted for replicating tissue-specific stiffness, enabling precise control over cell-matrix interactions. The surface functionalization of substrate materials, including collagen, polydopamine, and fibronectin, enhances bioactivity and fibroblast adhesion. Key mechanotransduction pathways, such as integrin signaling and YAP/TAZ activation, are related to regulating fibroblast behaviors and inflammatory responses. The role of fibroblasts in driving chronic inflammatory diseases emphasizes their therapeutic potentials. Advances in ECM-modifying strategies, including tunable biomaterials and hydrogel-based therapies, are explored for applications in tissue engineering, drug delivery, anti-inflammatory treatments, and diagnostic tools for the accurate diagnosis and prognosis of ECM stiffness-related inflammatory diseases. This review integrates mechanobiology with biomedical innovations, providing a comprehensive prognosis of fibroblast responses to ECM stiffness and outlining future directions for targeted therapies.

Technological constraints limit 3D printing of collagen structures with complex trabecular shapes. However, the Freeform Reversible Embedding of Suspended Hydrogels (FRESH) method may allow for precise 3D printing of porous collagen scaffolds that carry the potential for repairing critical size bone defects.

Collagen type I scaffolds mimicking trabecular bone were fabricated through FRESH 3D printing and compared either with 2D collagen coatings or with 3D-printed polyethylene glycol diacrylate (PEGDA) scaffolds. The porosity of the printed scaffolds was visualized by confocal microscopy, the surface geometry of the scaffolds was investigated by scanning electron microscopy (SEM), and their mechanical properties were assessed with a rheometer. The osteoconductive properties of the different scaffolds were evaluated for up to four weeks by seeding and propagation of primary human osteoblasts (hOBs) or SaOS-2 cells. Intracellular alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) activities were measured, and cells colonizing scaffolds were stained for osteocalcin (OCN).

The FRESH technique enables printing of constructs at the millimetre scale using highly concentrated collagen, and the creation of stable trabecular structures that can support the growth osteogenic cells. FRESH-printed collagen scaffolds displayed an intricate and fibrous 3D network, as visualized by SEM, whereas the PEGDA scaffolds had a smooth surface. Amplitude sweep analyses revealed that the collagen scaffolds exhibited predominantly elastic behaviour, as indicated by higher storage modulus values relative to loss modulus values, while the degradation rate of collagen scaffolds was greater than PEGDA. The osteoconductive properties of collagen scaffolds were similar to those of PEGDA scaffolds but superior to 2D collagen, as verified by cell culture followed by analysis of ALP/LDH activity and OCN immunostaining.

Our findings suggest that FRESH-printed collagen scaffolds exhibit favourable mechanical, degradation and osteoconductive properties, potentially outperforming synthetic polymers such as PEGDA in bone tissue engineering applications.

Control over network chemistry and connectivity of hydrogels is critical for the generation of tunable material properties, including material degradation for applications such as tissue scaffolding and drug delivery. Here, the degradation of hydrogels employing different hydrolytically cleavable groups including benzamide and syringic acid-derived carbamates, kojic acid-derived carbonates, and kojic acid-derived esters under physiological conditions was studied. Tunability of the hydrogel network degradation was demonstrated by varying the hydrolytically degradable moiety, macromer functionality, and copolymerization with hydrolytically stable macromers. These hydrolytically labile macromers were introduced and cross-linked intracellularly to induce transient cellular quiescence in MCF10A cells, resulting in a highly tunable degradation mechanism that is shown to be capable of inducing reversible biostasis of cells with 60% of cells treated with the carbonate macromer returning to their proliferative state and rebounding in translational activity after 72 h, while the biological activity of the carbamate macromer-treated cells remained suppressed.

Myocardial infarction remains a leading cause of death worldwide due to the heart's limited regenerative capability and the current lack of viable therapeutic solutions. Therefore, there is an urgent need to develop effective treatment options to restore cardiac function after a heart attack. Stem cell-derived cardiac cells have been extensively utilised in cardiac tissue regeneration studies. However, the use of Matrigel as a substrate for the culture and maturation of these cells has been a major limitation for the translation of this research into clinical application. Hydrogels are emerging as a promising system to overcome this problem. They are biocompatible and can provide stem cells with a supportive scaffold that mimics the extracellular matrix, which is essential for repairing damaged tissue in the myocardium after an infarction. Thus, hydrogels provide an alternative and reproducible option in addressing myocardial infarction due to their unique potential therapeutic benefits. This review explores the different types of natural and synthetic polymers used to create hydrogels and their various delivery methods, the most common being via injection and cardiac patches and other applications such as bioprinting. Many challenges remain before hydrogels can be used in a clinical setting, but they hold great promise for the future of cardiac tissue regeneration.

Effective treatment of bone diseases is quite tricky due to the unique nature of bone tissue and the complexity of the bone repair process. In combination with biological materials, cells and biological factors can provide a highly effective and safe treatment strategy for bone repair and regeneration, especially based on these multifunctional hydrogel interface materials. However, itis still a challenge to formulate hydrogel materials with fascinating properties (e.g., biological activity, controllable biodegradability, mechanical strength, excellent cell/tissue adhesion, and controllable release properties) for their clinical applications in complex bone repair processes. In this review, we will highlight recent advances in developing functional interface hydrogels. We then discuss the barriers to  producing of functional hydrogel materials without sacrificing their inherent properties, and potential applications in cartilage and bone repair are discussed. Multifunctional hydrogel interface materials can serve as a fundamental building block for bone tissue engineering.

The engineering construction of the liver has attracted enormous attention. Organoids, as emerging miniature three-dimensional cultivation units, hold significant potential in the biomimetic simulation of liver structure and function. Despite notable successes, organoids still face limitations such as high variability and low maturity. To overcome these challenges, engineering strategies have been established to maintain organoid stability and enhance their efficacy, laying the groundwork for the development of advanced liver organoids. The present review comprehensively summarizes the construction of engineered liver organoids and their prospective applications in biomedicine. Initially, we briefly present the latest research progress on matrix materials that maintain the three-dimensional morphology of organoids. Next, we discuss the manipulative role of engineering technologies in organoid assembly. Additionally, we outline the impact of gene-level regulation on organoid growth and development. Further, we introduce the applications of liver organoids in disease modeling, drug screening and regenerative medicine. Lastly, we overview the current obstacles and forward-looking perspectives on the future of engineered liver organoids. We anticipate that ongoing innovations in engineered liver organoids will lead to significant advancements in medical applications.

Polymer-based scaffolds with bioactive materials offer great potential in bone tissue engineering. Polyethylene glycol diacrylate (PEGDA) scaffolds fabricated via liquid crystal display 3D printing technique lack inherent osteoconductivity. To improve such properties, chitosan of 10 and 20 wt% and nanohydroxyapatite (nHA) (3-10 wt%) were incorporated into PEGDA scaffolds. nHA, synthesized via wet chemical precipitation, had a particle size of 28 nm and exhibited low crystallinity, as confirmed by X-ray diffraction. PEGDA-chitosan-nHA scaffolds underwent post-curing and 70 % ethanol leaching treatment. The presence of chitosan and nHA in the composite scaffolds was confirmed by their characteristic peaks. TGA analyses further verified nHA content correlating to the intended amount. The scaffolds featured interconnected pores ranging from 2891 to 3382 μm and porosities between 35 and 56 %. The swelling percentage and compressive modulus were reported at ~71-93 % and 0.52-1.18 MPa, respectively. Notably, PEGDA-chitosan-nHA scaffolds showed enhanced in vitro efficacy than pure PEGDA scaffolds, by promoting better MG63 cell adhesion (p < 0.05), higher proliferation and alkaline phosphatase (ALP) activity, particularly in scaffolds with 20 wt% chitosan across all incubation periods in cell proliferation and early osteoblast differentiation studies. These findings suggest that PEGDA-chitosan-nHA scaffolds have promising potential for bone tissue engineering applications.

Polymer-based scaffolds have emerged as transformative materials in regenerative dentistry, enabling the restoration and replacement of dental tissues through tissue engineering approaches. These scaffolds, derived from natural and synthetic polymers, mimic the extracellular matrix to promote cellular attachment, proliferation, and differentiation. Natural polymers such as collagen, chitosan, and alginate offer biocompatibility and bioactivity, while synthetic alternatives like polylactic acid (PLA) and polycaprolactone (PCL) provide tunable mechanical properties and degradation rates. Recent advancements highlight the integration of bioactive molecules and nanotechnology to enhance the regenerative potential of these materials. Furthermore, developing hybrid scaffolds combining natural and synthetic polymers addresses biocompatibility and mechanical strength challenges, paving the way for patient-specific treatments. Innovations in 3D bioprinting and stimuli-responsive biomaterials are expected to refine scaffold design further, improving therapeutic precision and clinical outcomes. This review underscores the critical role of polymer-based scaffolds in advancing regenerative dentistry, focusing on their applications, advantages, and limitations.

Developing scaffolds supporting functional cell attachment and tissue growth is critical in basic cell research, tissue engineering, and regenerative medicine approaches. Though poly(ethylene glycol) (PEG) and its derivatives are attractive for hydrogels and scaffold fabrication, they often require bioactive modifications due to their bioinert nature. In this work, biomimetic synthesized conductive polypyrrole-poly(3,4-ethylenedioxythiophene) copolymer doped with poly(styrenesulfonate) (PPy-PEDOT:PSS) was used as a biocompatible coating for poly(ethylene glycol) diacrylate (PEGDA) hydrogel to support neuronal and muscle cells' attachment, activity, and differentiation. The synthesized copolymer was characterized by Raman spectroscopy and dynamic light scattering. Its electrochemical properties were studied using galvanostatic charge-discharge (GCD) and voltammetry. PPy-PEDOT:PSS-coated hydrogels were characterized by Raman spectroscopy and atomic force microscopy, and protein adsorption was assessed using a quartz crystal microbalance with dissipation monitoring. Attachment and differentiation of the ND7/23 neuron hybrid cell line and C2C12 myoblasts were evaluated by cell cytoskeleton staining and quantification of morphological parameters. Viability was assessed by live/dead staining using flow cytometry. Cortex neural activity was studied by calcium ion influx that could be detected through the dynamic fluorescence changes of Fluo-4. The PPy-PEDOT:PSS coating supported cell attachment and differentiation and was nontoxic to cells. Primary neurons attached and remained responsive to electrical stimulation. Altogether, the biocompatible copolymer PPy-PEDOT:PSS is a simple yet effective alternative for hydrogel coating and presents great potential as an interface for nervous and other electrically excitable tissues.

Cultured meat aims to produce meat mass by culturing cells and tissues based on the muscle regeneration mechanism, and is considered an alternative to raising and slaughtering livestock. Hydrogel building blocks are commonly used as substrates for cell culture in tissue engineering and cultured meat because of their high water content, biocompatibility, and similar three-dimensional (3D) environment to the cellular niche in vivo. With the characteristics of precise manipulation of fluids, microfluidics exhibits advantages in the fabrication of building blocks with different structures and components, which have been widely applied in tissue regeneration. Microfluidic building blocks show promising prospects in the field of cultured meat; however, few reviews on the application of microfluidic building blocks in cultured meat have been published. This review outlines the recent status and prospects of the use of microfluidic building blocks in cultured meat. Starting with the introduction of cells and materials for cultured meat tissue construction, we then describe the diverse structures of the fabricated building blocks, including microspheres, microfibers, and microsphere-microfiber hybrid systems. Next, the stacking strategies for tissue construction are highlighted in detail. Finally, challenges and future prospects for developing microfluidic building blocks for cultured meat are discussed.

Peripheral nerve injuries are common complications in surgical and dental practices, often resulting in functional deficiencies and reduced quality of life. Current treatment choices, such as autografts, have limitations, including donor site morbidity and suboptimal outcomes. Adipose-derived stem cells (ADSCs) have shown assuring regenerative potential due to their accessibility, ease of harvesting and propagation, and multipotent properties. This review investigates the therapeutic potential of ADSCs in peripheral nerve regeneration, focusing on their use in bioengineered nerve conduits and supportive microenvironments. The analysis is constructed on published case reports, organized reviews, and clinical trials from Phase I to Phase III that investigate ADSCs in managing nerve injuries, emphasizing both peripheral and orofacial applications. The findings highlight the advantages of ADSCs in promoting nerve regeneration, including their secretion of angiogenic and neurotrophic factors, support for cellular persistence, and supplementing scaffold-based tissue repair. The regenerative capabilities of ADSCs in peripheral nerve injuries offer a novel approach to augmenting nerve repair and functional recovery. The accessibility of adipose tissue and the minimally invasive nature of ADSC harvesting further encourage its prospective application as an autologous cell source in regenerative medicine. Future research is needed to ascertain standardized protocols and optimize clinical outcomes, paving the way for ADSCs to become a mainstay in nerve regeneration.

Glycosaminoglycans (GAGs) are ubiquitous components in the cartilage extracellular matrix (ECM). Ultrastructural arrangement of ECM and GAG-mediated interactions with collagen are known to govern the mechanics in articular cartilage, but these interactions are less clear in other cartilage types. Therefore, this article reviews the current literature on ultrastructure of articular, auricular, meniscal, and nasal septal cartilage, seeking insight into GAG-mediated interactions influencing mechanics. Ultrastructural features of these cartilages are discussed to highlight differences between them. GAG-mediated interactions are reviewed under two categories: interactions with chondrocytes and interactions with other fibrillar macromolecules of the ECM. Moreover, efforts to replicate GAG-mediated interactions to improve mechanical integrity of tissue-engineered cartilage constructs are discussed. In conclusion, studies exploring cartilage specific GAGs are poorly represented in the literature, and the ultrastructure of nasal septal and auricular cartilage is less studied compared with articular and meniscal cartilages. Understanding the contribution of GAGs in cartilage mechanics at the ultrastructural level and translating that knowledge to engineered cartilage will facilitate improvement of cartilage tissue engineering approaches.

Periodontitis, characterized by microbial dysbiosis and immune dysregulation, destroys tooth-supporting tissues and negatively affects overall health. Current strategies face significant challenges in restoring damaged tissues while halting periodontitis progression. In this study, we introduce a live biotherapeutic product (LBP) in an engineered living hydrogel for comprehensive periodontitis therapy. A dental blue light-responsive hydrogel (LRG) was fabricated to deliver and confine live Lactobacillus rhamnosus GG (LGG) in periodontal pockets, endowing the LRG with sustained antibacterial and immunomodulatory effects. The LRG was engineered through peptide modification to also promote tissue regeneration. Both in vitro and in vivo evaluations confirmed the effectiveness of this integrated therapeutic strategy, which combines antibacterial, anti-inflammatory, and regenerative properties with an underlying immunomodulatory mechanism that involves suppressor of cytokine signaling (SOCS)3 upregulation and the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway suppression in macrophages. Demonstrating a new paradigm, this proof of concept highlights the synergistic integration of live organisms and synthetic material engineering in a chairside treatment to address the multifaceted etiology of periodontitis.

Retinal diseases can severely impair vision and even lead to blindness, posing significant threats to both physical and mental health. Physical retinal regenerative therapies are poised to revolutionize the treatment of various disorders associated with blindness. However, these therapies must overcome the challenges posed by the protective inner and outer blood‒retinal barriers. Nanotechnology applications in ophthalmology have shown great potential in addressing the issue of drug delivery to the eye. Moreover, nanotechnology-based therapeutics can have profound clinical impacts on retinopathy, particularly retinal regeneration, thereby improving patient outcomes. Continuous advancements in nanotechnology are being applied to regenerate lost or damaged eye tissues and to treat vision loss and blindness caused by various retinal degenerative diseases. These approaches can be categorized into three main strategies: i) nanoparticles for delivering drugs, genes, and other essential substances; ii) nanoscaffolds for providing biocompatible support; and iii) nanocomposites for enhancing the functionality of primary or stem cells. The aim of this comprehensive review is to present the current understanding of nanotechnology-based therapeutics for retinal regeneration, with a focus on the perspective functions of nanomaterials.

Spinal cord injury (SCI) leaves a temporary or enduring motor, sensory, and autonomic function loss, significantly impacting the patient's quality of life. Given their biocompatibility, bioactivity, and tunable attributes, three-dimensional scaffolds frequently employ carbohydrates to facilitate spinal cord regeneration. These scaffolds have also been engineered to be novel local delivery platforms that present distinct advantages in the targeted transportation of drug candidates to the damaged spinal cord, ensuring the right dosage and duration of administration. Neurotrophic factors have emerged as promising therapeutic candidates, preserved neuron survival and encouraged severed axons repair, although their local and continuous delivery is believed to produce considerable spinal cord rehabilitation. This study aims to discuss breakthroughs in scaffold engineering, exploiting carbohydrates as an essential part of their structure, and highlight their impact on spinal cord regeneration and sustained neurotrophic factors delivery to treat SCI.

Three-dimensional ovarian tissue culture is a unique model to define the effects of molecules on folliculogenesis. Using this model, we determined that RGD-integrin interaction plays a role in antrum formation and theca cell differentiation.

We recently developed a three-dimensional (3D) ovarian tissue culture system supported by bacterial-derived dextran hydrogel. Arg-Gly-Asp (RGD) is an extracellular matrix-derived triple peptide. Immature ovarian tissues cultured in RGD-modified dextran hydrogel significantly promoted antral follicle growth and oocyte quality compared with those cultured in dextran hydrogel alone. In this study, we examined the mechanism of follicle growth stimulated by RGD treatment in the 3D system. First, we detected that direct contact between RGD-modified dextran hydrogel and ovarian interstitial cells is necessary to promote antral follicle growth. Therefore, we hypothesized that RGD stimulates antral follicle growth through RGD-binding integrin receptors expressed in the interstitial cell mass. Using quantitative PCR (qPCR) and immunochemical staining, we identified that integrins ⍺vβ3 and ⍺v5 are predominantly expressed in the ovarian interstitial compartment. To assess the effect of RGD-integrin interaction on follicle growth, ovarian tissues were cultured with cilengitide (Ci), an inhibitor specific for ⍺vβ3 and ⍺vβ5. Ci treatment suppressed RGD-induced follicle growth and oocyte quality in a dose-dependent manner. When the interstitial cell aggregates were cultured with RGD, cell migration and theca-related gene expression were significantly upregulated. Ci treatment dramatically suppressed these RGD-induced activities. In coculturing the interstitial aggregate and secondary follicles with RGD, migrating cells formed the outermost cell layers around the follicles, like theca layers, which were totally blocked by Ci treatment. In conclusion, our results suggest that RGD stimulates theca cell differentiation in the ovarian interstitial cells through integrins ⍺vβ3 and ⍺v5 to promote antral follicle growth in our 3D system.

Three-dimensional (3D) in vitro models enable us to understand cell behavior that is a better reflection of what occurs in vivo than 2D in vitro models. As a result, developing 3D models for extracellular matrix (ECM) has been growing exponentially. Most of the efforts for these 3D models are geared toward understanding cancer cells. An intricate network of cells that engages with cancer cells and can kill them are the immune cells, particularly cytotoxic T lymphocytes (CTLs). However, limited reports are available for 3D ECM mimics to understand CTL dynamics. Currently, we lack ECM mimetic hydrogels for immune cells, with sufficient control over variables, such as stiffness, to fully understand CTL dynamics in vitro. Here, we developed PEG-based hydrogels as ECM mimics for CTLs. The ECM mimics are targeted to mimic the stiffness of soft tissues where CTLs reside, migrate, and deliver their function. To understand cell-material interaction, we determined the porosity, biocompatibility, and stiffness of the ECM mimics. The ECM mimics have median pore sizes of 10.7 and 13.3 μm, close to the average nucleus size of CTLs (~8.6 μm), and good biocompatibility to facilitate cell migration. The stiffness of the ECM mimics corresponds to biologically relevant microenvironments such as lungs and kidneys. Using time-lapse fluorescence microscopy, 3D cell migration was imaged and measured. CTLs migrated faster in softer ECM mimic with larger pores, consistent with previous studies in collagen (the gold standard ECM mimic for CTLs). The work herein demonstrates that the PEG-based ECM mimic can serve as an in vitro tool to elucidate the cell dynamics of CTLs. Thus, this study opens possibilities to study the mechanics of CTLs in well-defined ECM mimic conditions in vitro.

Conditions such as congenital abnormalities, cancer, infections, and trauma can severely impact the integrity of the auricular cartilage, resulting in the need for a replacement structure. Current implants, carved from the patient's rib, involve multiple surgeries and carry risks of adverse events such as contamination, rejection, and reabsorption. Tissue engineering aims to develop lifelong auricular bioimplants using different methods, different cell types, growth factors and maintenance media formulations, and scaffolding materials compatible with the host. This review aims to examine the progress in auricular bioengineering, focusing on improvements derived from in vivo models and clinical trials, as well as the author's suggestions to enhance the methods. For this scope review, 30 articles were retrieved through Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, plus 6 manually selected articles. The methods reported in the articles were categorized into four levels according to the development phases: source of cells, cell media supplementation, scaffold, or scaffold-free methods, and experimental in vivo or clinical approaches. Many methods have demonstrated potential for the development of bioimplants; four clinical trials reported a structure like the external ear that could be maintained after overcoming post-transplant inflammation. However, several challenges must be solved, such as obtaining a structure that accurately replicates the shape and size of the patient's healthy contralateral auricle and improvements to avoid immunological rejection and resorption of the bioimplant.

Bioprinting has the potential to revolutionize tissue engineering and regenerative medicine, offering innovative solutions for complex medical challenges and addressing unmet clinical needs. However, traditionalin vitrobioprinting techniques face significant limitations, including difficulties in fabricating and implanting scaffolds with irregular shapes, as well as limited accessibility for rapid clinical application. To overcome these challenges,in-situbioprinting has emerged as a groundbreaking approach that enables the direct deposition of cells, biomaterials, and bioactive factors onto damaged organs or tissues, eliminating the need for pre-fabricated 3D constructs. This method promises a personalized, patient-specific approach to treatment, aligning well with the principles of precision medicine. The success ofin-situbioprinting largely depends on the advancement of bioinks, which are essential for maintaining cell viability and supporting tissue development. Recent innovations in hand-held bioprinting devices and robotic arms have further enhanced the flexibility ofin-situbioprinting, making it applicable to various tissue types, such as skin, hair, muscle, bone, cartilage, and composite tissues. This review examinesin-situbioprinting techniques, the development of smart, multifunctional bioinks, and their essential properties for promoting cell viability and tissue growth. It highlights the versatility and recent advancements inin-situbioprinting methods and their applications in regenerating a wide range of tissues and organs. Furthermore, it addresses the key challenges that must be overcome for broader clinical adoption and propose strategies to advance these technologies toward mainstream medical practice.

Microgels show advantages over bulk hydrogels due to convenient control over microgel size and composition, and the ability to use microgels to modularly construct larger hierarchical scaffold hydrogel materials. Here, supramolecular chemistry is used to formulate supramolecular polymer, dynamic microgels solely held together by non-covalent interactions. Four-fold hydrogen bonding ureido-pyrimidinone (UPy) monomers with different functionalities are applied to precisely tune microgel properties in a modular way, via variations in monomer concentration, bifunctional crosslinker ratio, and the incorporation of supramolecular dyes and peptides. Functionalization with a bioactive supramolecular cell-adhesive peptide induced selectivity of cells toward the bioactive microgels over non-active, non-functionalized versions. Importantly, the supramolecular microgels can also be applied as microscale building blocks into supramolecular bulk macrogels with tunable dynamic behavior: a robust and weak macrogel, where the micro- and macrogels are composed of similar molecular building blocks. In a robust macrogel, microgels act as modular micro-building blocks, introducing multi-compartmentalization, while in a weak macrogel, microgels reinforce and enhance mechanical properties. This work demonstrates the potential to modularly engineer higher-length-scale structures using small molecule supramolecular monomers, wherein microgels serve as versatile and modular micro-building units.

Pancreatic adenocarcinoma (PDAC) is the predominant form of pancreatic cancer and one of the leading causes of cancer-related death worldwide, with an extremely poor prognosis after diagnosis. High mortality from PDAC arises partly due to late diagnosis resulting from a lack of early-stage biomarkers and due to chemotherapeutic drug resistance, which arises from a highly fibrotic stromal response known as desmoplasia. Desmoplasia alters tissue mechanics, which triggers changes in cell mechanosensing and leads to dysregulated transcriptional activity and disease phenotypes. Hydrogels are effective in vitro models to mimic mechanical changes in tissue mechanics during PDAC progression and to study the influence of these changes on mechanosensitive cell responses. Despite the complex biophysical changes that occur within the PDAC microenvironment, carefully designed hydrogels can very closely recapitulate these properties during PDAC progression. Hydrogels are relatively inexpensive, highly reproducible and can be designed in a humanised manner to increase their relevance for human PDAC studies. In vivo models have some limitations, including species-species differences, high variability, expense and legal/ethical considerations, which make hydrogel models a promising alternative. Here, we comprehensively review recent advancements in hydrogel bioengineering for developing our fundamental understanding of mechanobiology in PDAC, which is critical for informing advanced therapeutics.

Thiol-norbornene photoclick hydrogels are highly efficient in tissue engineering applications due to their fast gelation, cytocompatibility, and tunability. In this work, we utilized the advantageous features of polyethylene glycol (PEG)-thiol-ene resins to enable fabrication of complex and heterogeneous tissue scaffolds using 3D bioprinting and in-air drop encapsulation techniques. We demonstrated that photoclickable PEG-thiol-ene resins could be tuned by varying the ratio of PEG-dithiol to PEG norbornene to generate a wide range of mechanical stiffness (0.5-12 kPa) and swelling ratios. Importantly, all formulations maintained a constant, rapid gelation time (<0.5 s). We used this resin in biological projection microstereolithography (BioPµSL) to print complex structures with geometric fidelity and demonstrated biocompatibility by printing cell-laden microgrids. Moreover, the rapid gelling kinetics of this resin permitted high-throughput fabrication of tunable, cell-laden microgels in air using a biological in-air drop encapsulation apparatus (BioIDEA). We demonstrated that these microgels could support cell viability and be assembled into a gradient structure. This PEG-thiol-ene resin, along with BioPµSL and BioIDEA technology, will allow rapid fabrication of complex and heterogeneous tissues that mimic native tissues with cellular and mechanical gradients. The engineered tissue scaffolds with a controlled microscale porosity could be utilized in applications including gradient tissue engineering, biosensing, andin vitrotissue models.

Chronic diseases, including diabetes, cardiovascular diseases, and microvascular complications, contribute significantly to global morbidity and mortality. Current monitoring tools such as glucometers and continuous glucose monitors only measure one analyte; multiplexing technologies offer a promising approach for monitoring multiple biomarkers, enabling the management of comorbidities and providing more comprehensive disease insights. In this work, we describe a miniaturized optical "barcode" sensor with high biocompatibility for the continuous monitoring of glucose and oxygen. This enzymatic sensor relies on oxygen consumption in proportion to local glucose levels and the phosphorescence reporting of tissue oxygen with a lifetime-based probe. The sensor was specifically designed to operate in a tissue environment with low levels of dissolved oxygen. The barcode sensor consists of a poly(ethylene glycol) diacrylate (PEGDA) hydrogel with four discrete compartments separately filled with glucose- or oxygen-sensing phosphorescent microparticles. We evaluated the response of the barcode hydrogels to fluctuating glucose levels over the physiological range under low oxygen conditions, demonstrating the controlled tuning of dynamic range and sensitivity. Moreover, the barcode sensor exhibited remarkable storage stability over 12 weeks, along with full reversibility and excellent reproducibility (∼6% variability in the phosphorescence lifetime) over nearly 50 devices. Electron beam sterilization had a negligible effect on the glucose response of the barcode sensors. Furthermore, our investigation revealed minimal phosphorescence lifetime changes in oxygen compartments while exhibiting increased lifetime in glucose-responsive compartments when subjected to alternating glucose concentrations (0 and 200 mg/dL), showcasing the sensor's multianalyte sensing capabilities without crosstalk between compartments. Additionally, the evaluation of chronic tissue response to sensors inserted in pigs revealed the appropriate biocompatibility of the barcodes as well as excellent material stability over many months. These findings support further development of similar technologies for introducing optical assays for multiple biomarkers that can provide continuous or on-demand feedback to individuals to manage chronic conditions.

Supramolecular peptide hydrogels (SPHs) consist of peptides containing hydrogelators and functional epitopes, which can first self-assemble into nanofibers and then physically entangle together to form dynamic three-dimensional networks. Their porous structures, excellent bioactivity, and high dynamicity, similar to an extracellular matrix (ECM), have great potential in artificial ECM. The properties of the hydrogel are largely dependent on peptides. The noncovalent interactions among hydrogelators drive the formation of assemblies and further transition into hydrogels, while bioactive epitopes modulate cell-cell and cell-ECM interactions. Therefore, SPHs can support cell growth, making them ideal biomaterials for ECM mimics. This Review outlines the classical molecular design of SPHs from hydrogelators to functional epitopes and summarizes the recent advancements of SPHs as artificial ECMs in nervous system repair, wound healing, bone and cartilage regeneration, and organoid culture. This emerging SPH platform could provide an alternative strategy for developing more effective biomaterials for tissue engineering.

This review considers fully three-dimensional biomaterial environments of varying complexity as these pertain to research on the placenta. The developments in placental cell sources are first considered, along with the corresponding maternal cells with which the trophoblast interact. We consider biomaterial sources, including hybrid and composite biomaterials. Properties and characterization of biomaterials are discussed in the context of material design for specific placental applications. The development of increasingly complicated three-dimensional structures includes examples of advanced fabrication methods such as microfluidic device fabrication and 3D bioprinting, as utilized in a placenta context. The review finishes with a discussion of the potential for in vitro, three-dimensional placenta research to address health disparities and sexual dimorphism, especially in light of the exciting recent changes in the regulatory environment for in vitro devices.

The biochemical and biophysical properties of the extracellular matrix (ECM) play a pivotal role in regulating cellular behaviors such as proliferation, migration, and differentiation. Engineered protein-based hydrogels, with highly tunable multifunctional properties, have the potential to replicate key features of the native ECM. Formed by self-assembly or crosslinking, engineered protein-based hydrogels can induce a range of cell behaviors through bioactive and functional domains incorporated into the polymer backbone. Using recombinant techniques, the amino acid sequence of the protein backbone can be designed with precise control over the chain-length, folded structure, and cell-interaction sites. In this review, the modular design of engineered protein-based hydrogels from both a molecular- and network-level perspective are discussed, and summarize recent progress and case studies to highlight the diverse strategies used to construct biomimetic scaffolds. This review focuses on amino acid sequences that form structural blocks, bioactive blocks, and stimuli-responsive blocks designed into the protein backbone for highly precise and tunable control of scaffold properties. Both physical and chemical methods to stabilize dynamic protein networks with defined structure and bioactivity for cell culture applications are discussed. Finally, a discussion of future directions of engineered protein-based hydrogels as biomimetic cellular scaffolds is concluded.

Limbal stem cell deficiency (LSCD) is a complex disease of the cornea resulting from dysfunction and/or loss of limbal stem cells (LSCs) and their niche. Most patients with LSCD cannot be treated by conventional corneal transplants because the donor tissue lacks the LSCs necessary for corneal epithelial regeneration. Successful treatment of LSCD depends on effective stem cell transplantation to the ocular surface for replenishment of the LSC reservoir. Thus, stem cell therapies employing carrier substrates for LSCs have been widely explored. Hydrogel biomaterials have many favorable characteristics, including hydrophilicity, flexibility, cytocompatibility, and optical properties suitable for the transplantation of LSCs. Therefore, due to these properties, along with the necessary signals for stem cell proliferation and differentiation, hydrogels are ideal carrier substrates for LSCD treatment. This review summarizes the use of different medical-type hydrogels in LSC transplantation from 2001 to 2024. First, a brief background of LSCD is provided. Then, studies that employed various hydrogel scaffolds as LSC carriers are highlighted to provide a multimodal strategic reference for LSCD treatment. Finally, an analysis of prospective future developments and challenges in the field of hydrogels as LSC carriers for treating LSCD is presented.

The tumor microenvironment (TME) assumes a pivotal role in the treatment of oncological diseases, given its intricate interplay of diverse cellular components and extracellular matrices. This dynamic ecosystem poses a serious challenge to traditional research methods in many ways, such as high research costs, inefficient translation, poor reproducibility, and low modeling success rates. These challenges require the search for more suitable research methods to accurately model the TME, and the emergence of 3D bioprinting technology is transformative and an important complement to these traditional methods to precisely control the distribution of cells, biomolecules, and matrix scaffolds within the TME. Leveraging digital design, the technology enables personalized studies with high precision, providing essential experimental flexibility. Serving as a critical bridge between in vitro and in vivo studies, 3D bioprinting facilitates the realistic 3D culturing of cancer cells. This comprehensive article delves into cutting-edge developments in 3D bioprinting, encompassing diverse methodologies, biomaterial choices, and various 3D tumor models. Exploration of current challenges, including limited biomaterial options, printing accuracy constraints, low reproducibility, and ethical considerations, contributes to a nuanced understanding. Despite these challenges, the technology holds immense potential for simulating tumor tissues, propelling personalized medicine, and constructing high-resolution organ models, marking a transformative trajectory in oncological research.

A series of hybrid hydrogels of poly(ethylene glycol) (PEG) were synthesized using gelatin as a crosslinker and investigated for controlled delivery of the first-generation cephalosporin antibiotic, Cefazedone sodium (CFD). A commercially available 4-arm-PEG-OH was first modified to obtain four-arm-PEG-succinimidyl glutarate (4-arm-PEG-SG), which formed the gelatin-PEG composite hydrogels (SnNm) through crosslinking with gelatin. To regulate the drug delivery, SnNm hydrogels with various solid contents and crosslinking degrees were prepared. The effect of solid contents and crosslinking degrees on the thermal, mechanical, swelling, degradation, and drug release properties of the hydrogels were intensively investigated. The results revealed that increasing the crosslinking degree and solid content of SnNm could not only enhance the thermal stability, swelling ratio (SR), and compression resistance capacity of SnNm but also prolong the degradation and drug release times. The release kinetics of the SnNm hydrogels were found to follow the first-order model, suggesting that the transport rate of CFD within the matrix of hydrogels is proportional to the concentration of the drug where it is located. Specifically, S1N1-III showed 90% mass loss after 60 h of degradation and a sustained release duration of 72 h. The cytotoxicity assay using the MTT method revealed that cell viability rates of S1N1 were higher than 95%, indicating excellent cytocompatibility. This study offers new insights and methodologies for the development of hydrogels as biomedical composite materials.

The development of hydrophobic poly(ethylene glycol) (PEG) hydrogels, which are typically hydrophilic, could significantly enhance their application as artificial extracellular matrices. In this study, we designed PEG hydrogels with enhanced hydrophobicity through gel-gel phase separation (GGPS), a phenomenon that uniquely enhances hydrophobicity under ambient conditions, and we elucidated the pivotal role of elasticity in this process. We hypothesized that increased elasticity would amplify GGPS, thereby improving the hydrophobicity and cell adhesion on PEG hydrogel surfaces, despite their inherent hydrophilicity. To test this hypothesis, we engineered dilute oligo-PEG gels via a two-step process, creating polymer networks from tetra-PEG clusters with multiple reaction points. These oligo-PEG gels exhibited significantly higher elasticity, turbidity, and shrinkage upon water immersion compared to dilute PEG gels. Detailed characterization through confocal laser scanning microscopy, rheological measurements, and cell adhesion assays revealed distinct biphasic structures, increased hydrophobicity, and enhanced cell attachability in the dilute oligo-PEG gels. Our findings confirm that elasticity is crucial for effective GGPS, providing a novel method for tailoring hydrogel properties without chemical modification. This research introduces a new paradigm for designing biomaterials with improved cell-scaffolding capabilities, offering significant potential for tissue engineering and regenerative medicine.

Fractional viscoelastic models provide an excellent description of rheological data for polymer systems with power-law behaviour. However, the physical interpretation of their model parameters, which carry fractional units of time, often remains elusive. We show that for poly(ethylene oxide) (PEO) solutions, the fractional Maxwell model (FMM) requires much fewer model parameters than the classical generalized Maxwell model for a good description of the data and that it can be applied consistently to solutions with varying degrees of viscoelasticity. Despite their fractional units, the parameters exhibit scaling laws similar to classical parameters as a function of polymer concentration.

The drive for minimally invasive endodontic treatment strategies has shifted focus from technically complex and destructive root canal treatments towards more conservative vital pulp treatment. However, novel approaches to maintaining dental pulp vitality after disease or trauma will require the development of innovative, biologically-driven regenerative medicine strategies. For example, cell-homing and cell-based therapies have recently been developed in vitro and trialled in preclinical models to study dental pulp regeneration. These approaches utilise natural and synthetic scaffolds that can deliver a range of bioactive pharmacological epigenetic modulators (HDACis, DNMTis, and ncRNAs), which are cost-effective and easily applied to stimulate pulp tissue regrowth. Unfortunately, many biological factors hinder the clinical development of regenerative therapies, including a lack of blood supply and poor infection control in the necrotic root canal system. Additional challenges include a need for clinically relevant models and manufacturing challenges such as scalability, cost concerns, and regulatory issues. This review will describe the current state of bioactive-biomaterial/scaffold-based engineering strategies to stimulate dentine-pulp regeneration, explicitly focusing on epigenetic modulators and therapeutic pharmacological inhibition. It will highlight the components of dental pulp regenerative approaches, describe their current limitations, and offer suggestions for the effective translation of novel epigenetic-laden bioactive materials for innovative therapeutics.