Upcycling plastic waste into fully recyclable composites through cold sintering.

Plastics have substantial societal benefits, but their widespread use has led to a critical waste management challenge. While mechanical recycling dominates the reuse of post-consumer plastics, it is limited in efficacy, especially for composites. To address this, we propose a direct reprocessing approach that enables the creation of hybrid, long-lasting, and durable composites from difficult-to-recycle plastics. This approach utilizes cold sintering, a process that consolidates inorganic powders through fractional dissolution and precipitation at temperatures far below conventional sintering; these temperatures are compatible with plastic processing. We show that this process can create inorganic-matrix composites with significant enhancements in tensile strength and toughness over pure gypsum, which is commonly found in construction waste. These composites can be recycled multiple times through direct reprocessing with the addition of only water as a processing promoter. This approach to recycling leads to composites with orders of magnitude lower energy demand, global warming potential, and water demand, when compared against common construction products. Altogether, we demonstrate the potential for cold sintering to integrate waste into high-performance recyclable composites.

Accelerating Patterned Vascularization Using Granular Hydrogel Scaffolds and Surgical Micropuncture.

Bulk hydrogel scaffolds are common in reconstructive surgery. They allow for the staged repair of soft tissue loss by providing a base for revascularization. Unfortunately, they are limited by both slow and random vascularization, which may manifest as treatment failure or suboptimal repair. Rapidly inducing patterned vascularization within biomaterials has profound translational implications for current clinical treatment paradigms and the scaleup of regenerative engineering platforms. To address this long-standing challenge, a novel microsurgical approach and granular hydrogel scaffold (GHS) technology are co-developed to hasten and pattern microvascular network formation. In surgical micropuncture (MP), targeted recipient blood vessels are perforated using a microneedle to accelerate cell extravasation and angiogenic outgrowth. By combining MP with an adjacent GHS with precisely tailored void space architecture, microvascular pattern formation as assessed by density, diameter, length, and intercapillary distance is rapidly guided. This work opens new translational opportunities for microvascular engineering, advancing reconstructive surgery, and regenerative medicine.

Iron inhibits glioblastoma cell migration and polarization.

Glioblastoma is one of the deadliest malignancies facing modern oncology today. The ability of glioblastoma cells to diffusely spread into neighboring healthy brain makes complete surgical resection nearly impossible and contributes to the recurrent disease faced by most patients. Although research into the impact of iron on glioblastoma has addressed proliferation, there has been little investigation into how cellular iron impacts the ability of glioblastoma cells to migrate-a key question, especially in the context of the diffuse spread observed in these tumors. Herein, we show that increasing cellular iron content results in decreased migratory capacity of human glioblastoma cells. The decrease in migratory capacity was accompanied by a decrease in cellular polarization in the direction of movement. Expression of CDC42, a Rho GTPase that is essential for both cellular migration and establishment of polarity in the direction of cell movement, was reduced upon iron treatment. We then analyzed a single-cell RNA-seq dataset of human glioblastoma samples and found that cells at the tumor periphery had a gene signature that is consistent with having lower levels of cellular iron. Altogether, our results suggest that cellular iron content is impacting glioblastoma cell migratory capacity and that cells with higher iron levels exhibit reduced motility.

Dynein-Powered Cell Locomotion Guides Metastasis of Breast Cancer.

The principal cause of death in cancer patients is metastasis, which remains an unresolved problem. Conventionally, metastatic dissemination is linked to actomyosin-driven cell locomotion. However, the locomotion of cancer cells often does not strictly line up with the measured actomyosin forces. Here, a complementary mechanism of metastatic locomotion powered by dynein-generated forces is identified. These forces arise within a non-stretchable microtubule network and drive persistent contact guidance of migrating cancer cells along the biomimetic collagen fibers. It is also shown that the dynein-powered locomotion becomes indispensable during invasive 3D migration within a tissue-like luminal network formed by spatially confining granular hydrogel scaffolds (GHS) made up of microscale hydrogel particles (microgels). These results indicate that the complementary motricity mediated by dynein is always necessary and, in certain instances, sufficient for disseminating metastatic breast cancer cells. These findings advance the fundamental understanding of cell locomotion mechanisms and expand the spectrum of clinical targets against metastasis.

Mussel-Inspired Nanocellulose Coating for Selective Neodymium Recovery.

Neodymium (Nd) is one of the most in-demand rare earth elements (REEs) for developing the next generation of magnetic medical devices and clean energy. Eco-friendly and sustainable nanotechnology for REE recovery may be highly suitable to address the limited global supply while minimizing the environmental footprints of current practice, such as solvent extraction. Here, we present a novel one-step mussel-inspired nanocellulose coating (MINC) using bifunctional hairy cellulose nanocrystals (BHCNC), bearing dialdehyde and dicarboxylate groups. The dialdehyde groups enable dopamine-mediated orthogonal conjugation of BHCNC to substrates, such as microparticles, while the high content of dicarboxylate groups yields high-capacity and selective Nd removal against ferric, calcium, and sodium ions. To the best of our knowledge, the MINC-treated substrate provides the most rapid selective removal and recovery of Nd ions even at low Nd concentrations with a capacity that is among the highest reported values. We envision that the MINC will provide new opportunities in developing next-generation bio-based materials and interfaces for the sustainable recovery of REEs and other precious elements.

Injectable, Antibacterial, and Hemostatic Tissue Sealant Hydrogels.

Hemorrhage and bacterial infections are major hurdles in the management of life-threatening surgical wounds. Most bioadhesives for wound closure lack sufficient hemostatic and antibacterial properties. Furthermore, they suffer from weak sealing efficacy, particularly for stretchable organs, such as the lung and bladder. Accordingly, there is an unmet need for mechanically robust hemostatic sealants with simultaneous antibacterial effects. Here, an injectable, photocrosslinkable, and stretchable hydrogel sealant based on gelatin methacryloyl (GelMA), supplemented with antibacterial zinc ferrite (ZF) nanoparticles and hemostatic silicate nanoplatelets (SNs) for rapid blood coagulation is nanoengineered. The hydrogel reduces the in vitro viability of Staphylococcus aureus by more than 90%. The addition of SNs (2% w/v) and ZF nanoparticles (1.5 mg mL-1 ) to GelMA (20% w/v) improves the burst pressure of perforated ex vivo porcine lungs by more than 40%. Such enhancement translated to ≈250% improvement in the tissue sealing capability compared with a commercial hemostatic sealant, Evicel. Furthermore, the hydrogels reduce bleeding by ≈50% in rat bleeding models. The nanoengineered hydrogel may open new translational opportunities for the effective sealing of complex wounds that require mechanical flexibility, infection management, and hemostasis.

Dynein-Powered Cell Locomotion Guides Metastasis of Breast Cancer.

Metastasis is a principal cause of death in cancer patients, which remains an unresolved fundamental and clinical problem. Conventionally, metastatic dissemination is linked to the actomyosin-driven cell locomotion. However, locomotion of cancer cells often does not strictly line up with the measured actomyosin forces. Here, we identify a complementary mechanism of metastatic locomotion powered by the dynein-generated forces. These forces that arise within a non-stretchable microtubule network drive persistent contact guidance of migrating cancer cells along the biomimetic collagen fibers. We also show that dynein-powered locomotion becomes indispensable during invasive 3D migration within a tissue-like luminal network between spatially confining hydrogel microspheres. Our results indicate that the complementary contractile system of dynein motors and microtubules is always necessary and in certain instances completely sufficient for dissemination of metastatic breast cancer cells. These findings advance fundamental understanding of cell locomotion mechanisms and expand the spectrum of clinical targets against metastasis.

Colloidal aspects of calcium carbonate scaling in water-in-oil emulsions: A fundamental study using droplet-based microfluidics.

HYPOTHESIS: As a mainstream process in the extraction and recovery of crude oil, water is injected into reservoirs in the so-called waterflooding process to facilitate the oil displacement through the wellbore, typically generating water-in-oil (W/O) emulsions. Based on economic considerations, sea water is used in the flooding process; however, the ionic incompatibility between the injected water and the formation water inside the reservoir may precipitate sparingly-soluble inorganic salts (scale). We hypothesize that calcium carbonate (CaCO3) scale dynamically interacts with cationic surfactants in W/O emulsions, resulting in (i) scale growth retardation and (ii) emulsion destabilization. EXPERIMENTS: We developed stable W/O emulsions via combining droplet-based microfluidics with multifactorial optimizations to investigate the influence of emulsion properties, such as surfactant type and concentrations, temperature, and pH, as well as calcium ions on the CaCO3 scaling kinetics and emulsion stability. The CaCO3 scale was characterized based on particle size and charge, lattice structure, interactions with the surfactant, and time-dependent effects on emulsion stability. FINDINGS: The interfacial interactions between the cationic surfactant (cetyltrimethylammonium bromide, CTAB) and CaCO3 retarded scale growth rate, decreased crystal size, and destabilized emulsion within hours as a result of surfactant depletion at the water-oil interface. The surfactant did not affect the crystal structure of scale, which was formed as the most thermodynamically stable crystalline polymorph, calcite, at the ambient condition. This fundamental study may open new opportunities for engineering stable W/O emulsions, e.g., for enhanced oil recovery (EOR), and developing scale-resistant multiphase flows.

Tissue adhesive hemostatic microneedle arrays for rapid hemorrhage treatment.

Blood loss by hemorrhaging wounds accounts for over one-third of ∼5 million trauma fatalities worldwide every year. If not controlled in a timely manner, exsanguination can take lives within a few minutes. Developing new biomaterials that are easy to use by non-expert patients and promote rapid blood coagulation is an unmet medical need. Here, biocompatible, and biodegradable microneedle arrays (MNAs) based on gelatin methacryloyl (GelMA) biomaterial hybridized with silicate nanoplatelets (SNs) are developed for hemorrhage control. The SNs render the MNAs hemostatic, while the needle-shaped structure increases the contact area with blood, synergistically accelerating the clotting time from 11.5 min to 1.3 min in vitro. The engineered MNAs reduce bleeding by ∼92% compared with the untreated injury group in a rat liver bleeding model. SN-containing MNAs outperform the hemostatic effect of needle-free patches and a commercial hemostat in vivo via combining micro- and nanoengineered features. Furthermore, the tissue adhesive properties and mechanical interlocking support the suitability of MNAs for wound closure applications. These hemostatic MNAs may enable rapid hemorrhage control, particularly for patients in developing countries or remote areas with limited or no immediate access to hospitals.

Nanoengineering the Redispersibility of Cellulose Nanocrystals.

Enhancing the redispersibility of dried colloidal particles to yield stable dispersions after rehydration is a persistent challenge in the sustainable processing of nanocelluloses due to hydrogen bonding-induced irreversible aggregation. Programming nanocelluloses, such as cellulose nanocrystals (CNC), with moieties that enable colloidal repulsion after rehydration may address this challenge and contribute to the United Nation (UN)'s sustainable development goals (SDGs) of urban development and sustainable living (SDGs 9 and 11) and cradle-to-cradle processing (SDG 12). We hypothesize that imparting electrosteric repulsion to CNC via polyanionic disordered cellulose chains (hairs) protruding from each end may render the dried nanocrystals highly redispersible in aqueous media. Anionic hairy CNC (AHCNC), that is, CNC decorated with dicarboxylated cellulose (DCC) chains, were synthesized by the preferential, successive periodate/chlorite oxidation of the disordered regions of cellulose fibrils, bearing >5 mmol of carboxylate groups per gram. The colloidal properties of AHCNC were compared with those of sulfate half-ester group-functionalized CNC and TEMPO-oxidized CNC (TOCNC) after redispersion in aqueous media, followed by comparing the redispersibility of AHCNC and CNC in aqueous solutions containing monovalent or divalent cations and at varying pH. The AHCNC had remarkable aqueous redispersibility even at high ionic strengths and extreme pH. The unique redispersibility mechanism of dried AHCNC relies on the synergistic steric and electrostatic repulsion forces, recuperated upon the rehydration of DCC. This work may open new opportunities for more sustainable and cost-effective handling and processing of nanocelluloses.

Gelatin Methacryloyl Granular Hydrogel Scaffolds: High-throughput Microgel Fabrication, Lyophilization, Chemical Assembly, and 3D Bioprinting.

The emergence of granular hydrogel scaffolds (GHS), fabricated via assembling hydrogel microparticles (HMPs), has enabled microporous scaffold formation in situ. Unlike conventional bulk hydrogels, interconnected microscale pores in GHS facilitate degradation-independent cell infiltration as well as oxygen, nutrient, and cellular byproduct transfer. Methacryloyl-modified gelatin (GelMA), a (photo)chemically crosslinkable, protein-based biopolymer containing cell adhesive and biodegradable moieties, has widely been used as a cell-responsive/instructive biomaterial. Converting bulk GelMA to GHS may open a plethora of opportunities for tissue engineering and regeneration. In this article, we demonstrate the procedures of high-throughput GelMA microgel fabrication, conversion to resuspendable dry microgels (micro-aerogels), GHS formation via the chemical assembly of microgels, and granular bioink fabrication for extrusion bioprinting. We show how a sequential physicochemical treatment via cooling and photocrosslinking enables the formation of mechanically robust GHS. When light is inaccessible (e.g., during deep tissue injection), individually crosslinked GelMA HMPs may be bioorthogonally assembled via enzymatic crosslinking using transglutaminases. Finally, three-dimensional (3D) bioprinting of microporous GHS at low HMP packing density is demonstrated via the interfacial self-assembly of heterogeneously charged nanoparticles.

Recent advances and challenges in recycling and reusing biomedical materials.

Medical waste has increased in the past 3 years as a result of the coronavirus disease 2019 (COVID-19) pandemic. This condition is expected to exacerbate due to the growing healthcare markets and aging population, posing health threats to the public via environmental footprints. To alleviate these impacts, there is an urgent need for medical waste management. This article highlights the drawbacks of current disposal methods and the potential of medical waste reuse and recycling, emphasizing the processes, materials, and chemistry involved in each practice. Further discussion is provided on the chemical and mechanical recycling of plastics as the dominating material in biomedical applications, and possible strategies and challenges in recycling and reusing biomedical materials are explored in this review.

Ion Exchange Biomaterials to Capture Daptomycin and Prevent Resistance Evolution in Off-Target Bacterial Populations.

Daptomycin (DAP), a cyclic anionic lipopeptide antibiotic, is among the last resorts to treat multidrug-resistant Gram-positive bacterial infections, caused by vancomycin-resistant Enterococcus faecium or methicillin-resistant Staphylococcus aureus. DAP is administered intravenously, and via biliary excretion, ∼5-10% of the intravenous DAP dose arrives in the gastrointestinal (GI) tract where it drives resistance evolution in the off-target populations of E. faecium bacteria. Previously, we have shown in vivo that the oral administration of cholestyramine, an ion exchange biomaterial (IXB) sorbent, prevents DAP treatment from enriching DAP resistance in the populations of E. faecium shed from mice. Here, we investigate the biomaterial-DAP interfacial interactions to uncover the antibiotic removal mechanisms. The IXB-mediated DAP capture from aqueous media was measured in controlled pH/electrolyte solutions and in the simulated intestinal fluid (SIF) to uncover the molecular and colloidal mechanisms of DAP removal from the GI tract. Our findings show that the IXB electrostatically adsorbs the anionic antibiotic via a time-dependent diffusion-controlled process. Unsteady-state diffusion-adsorption mass balance describes the dynamics of adsorption well, and the maximum removal capacity is beyond the electric charge stoichiometric ratio because of DAP self-assembly. This study may open new opportunities for optimizing cholestyramine adjuvant therapy to prevent DAP resistance, as well as designing novel biomaterials to remove off-target antibiotics from the GI tract.

A Cohesive Shear-Thinning Biomaterial for Catheter-Based Minimally Invasive Therapeutics.

Shear-thinning hydrogels are suitable biomaterials for catheter-based minimally invasive therapies; however, the tradeoff between injectability and mechanical integrity has limited their applications, particularly at high external shear stress such as that during endovascular procedures. Extensive molecular crosslinking often results in stiff, hard-to-inject hydrogels that may block catheters, whereas weak crosslinking renders hydrogels mechanically weak and susceptible to shear-induced fragmentation. Thus, controlling molecular interactions is necessary to improve the cohesion of catheter-deployable hydrogels. To address this material design challenge, we have developed an easily injectable, nonhemolytic, and noncytotoxic shear-thinning hydrogel with significantly enhanced cohesion via controlling noncovalent interactions. We show that enhancing the electrostatic interactions between weakly bound biopolymers (gelatin) and nanoparticles (silicate nanoplatelets) using a highly charged polycation at an optimum concentration increases cohesion without compromising injectability, whereas introducing excessive charge to the system leads to phase separation and loss of function. The cohesive biomaterial is successfully injected with a neuroendovascular catheter and retained without fragmentation in patient-derived three-dimensionally printed cerebral aneurysm models under a physiologically relevant pulsatile fluid flow, which would otherwise be impossible using the noncohesive hydrogel counterpart. This work sheds light on how charge-driven molecular and colloidal interactions in shear-thinning physical hydrogels improve cohesion, enabling complex minimally invasive procedures under flow, which may open new opportunities for developing the next generation of injectable biomaterials.

Nanoengineered Granular Hydrogel Bioinks with Preserved Interconnected Microporosity for Extrusion Bioprinting.

3D bioprinting of granular hydrogels comprising discrete hydrogel microparticles (microgels) may overcome the intrinsic structural limitations of bulk (nanoporous) hydrogel bioinks, enabling the fabrication of modular thick tissue constructs. The additive manufacturing of granular scaffolds has predominantly relied on highly jammed microgels to render the particulate suspensions shear yielding and extrudable. This inevitably compromises void spaces between microgels (microporosity), defeating rapid cell penetration, facile metabolite and oxygen transfer, and cell viability. Here, this persistent bottleneck is overcome by programming microgels with reversible interfacial nanoparticle self-assembly, enabling the fabrication of nanoengineered granular bioinks (NGB) with well-preserved microporosity, enhanced printability, and shape fidelity. The microporous architecture of bioprinted NGB constructs permits immediate post-printing 3D cell seeding, which may expand the library of bioinks via circumventing the necessity of bioorthogonality for cell-laden scaffold formation. This work opens new opportunities for the 3D bioprinting of tissue engineering microporous scaffolds beyond the traditional biofabrication window.

Assessing the aneurysm occlusion efficacy of a shear-thinning biomaterial in a 3D-printed model.

Metallic coil embolization is a common method for the endovascular treatment of visceral artery aneurysms (VAA) and visceral artery pseudoaneurysms (VAPA); however, this treatment is suboptimal due to the high cost of coils, incomplete volume occlusion, poor reendothelialization, aneurysm puncture, and coil migration. Several alternative treatment strategies are available, including stent flow diverters, glue embolics, gelfoam slurries, and vascular mesh plugs-each of which have their own disadvantages. Here, we investigated the in vitro capability of a shear-thinning biomaterial (STB), a nanocomposite hydrogel composed of gelatin and silicate nanoplatelets, for the minimally-invasive occlusion of simple necked aneurysm models. We demonstrated the injectability of STB through various clinical catheters, engineered an in vitro testing apparatus to independently manipulate aneurysm neck diameter, fluid flow rate, and flow waveform, and tested the stability of STB within the models under various conditions. Our experiments show that STB is able to withstand at least 1.89 Pa of wall shear stress, as estimated by computational fluid dynamics. STB is also able to withstand up to 10 mL s-1 pulsatile flow with a waveform mimicking blood flow in the human femoral artery and tolerate greater pressure changes than those in the human aorta. We ultimately found that our in vitro system was limited by supraphysiologic pressure changes caused by aneurysm models with low compliance.

A Readily Scalable, Clinically Demonstrated, Antibiofouling Zwitterionic Surface Treatment for Implantable Medical Devices.

Unlike growth on tissue, microbes can grow freely on implantable devices with minimal immune system intervention and often form resilient biofilms that continuously pump out pathogenic cells. The efficacy of antibiotics used to treat infection is declining due to increased rates of pathogenic resistance. A simple, one-step zwitterionic surface modification is developed to significantly reduce protein and microbial adhesion to synthetic materials and demonstrate the successful modification of several clinically relevant materials, including recalcitrant materials such as elastomeric polydimethylsiloxane. The treated surfaces exhibit robust adhesion resistance against proteins and microorganisms in both static and flow conditions. Furthermore, the surface treatment prevents the adhesion of mammalian fibroblast cells while displaying no cytotoxicity. To demonstrate the clinical efficacy of the novel technology in the real-world, a surface-treated, commercial silicone foley catheter is developed that is cleared for use by the U.S. Food and Drug Administration (K192034). 16 long-term catheterized patients received surface-treated catheters and completed a Patient Global Impression of Improvement (PGI-I) questionnaire. 10 out of 16 patients described their urinary tract condition post implantation as "much better" or "very much better" and 72% (n = 13) of patients desire to continue using the surface-treated catheter over conventional latex or silicone catheters.

Engineering hairy cellulose nanocrystals for chemotherapy drug capture.

Cancer is one of the leading causes of death worldwide, affecting millions of people every year. While chemotherapy remains one of the most common cancer treatments in the world, the severe side effects of chemotherapy drugs impose serious concerns to cancer patients. In many cases, the chemotherapy can be localized to maximize the drug effects; however, the drug systemic circulation induces undesirable side effects. Here, we have developed a highly efficient cellulose-based nanoadsorbent that can capture more than 6000 mg of doxorubicin (DOX), one of the most widely used chemotherapy drugs, per gram of the adsorbent at physiological conditions. Such drug capture capacity is more than 3200% higher than other nanoadsorbents, such as DNA-based platforms. We show how anionic hairy cellulose nanocrystals, also known as electrosterically stabilized nanocrystalline cellulose (ENCC), bind to positively charged drugs in human serum and capture DOX immediately without imposing any cytotoxicity and hemolytic effects. We elucidate how ENCC provides a remarkable platform for biodetoxification at varying pH, ionic strength, ion type, and protein concentration. The outcome of this research may pave the way for developing the next generation in vitro and in vivo drug capture additives and devices.

Nanoengineered Shear-Thinning Hydrogel Barrier for Preventing Postoperative Abdominal Adhesions.

More than 90% of surgical patients develop postoperative adhesions, and the incidence of hospital re-admissions can be as high as 20%. Current adhesion barriers present limited efficacy due to difficulties in application and incompatibility with minimally invasive interventions. To solve this clinical limitation, we developed an injectable and sprayable shear-thinning hydrogel barrier (STHB) composed of silicate nanoplatelets and poly(ethylene oxide). We optimized this technology to recover mechanical integrity after stress, enabling its delivery though injectable and sprayable methods. We also demonstrated limited cell adhesion and cytotoxicity to STHB compositions in vitro. The STHB was then tested in a rodent model of peritoneal injury to determine its efficacy preventing the formation of postoperative adhesions. After two weeks, the peritoneal adhesion index was used as a scoring method to determine the formation of postoperative adhesions, and STHB formulations presented superior efficacy compared to a commercially available adhesion barrier. Histological and immunohistochemical examination showed reduced adhesion formation and minimal immune infiltration in STHB formulations. Our technology demonstrated increased efficacy, ease of use in complex anatomies, and compatibility with different delivery methods, providing a robust universal platform to prevent postoperative adhesions in a wide range of surgical interventions.

Advances in bioactive glass-containing injectable hydrogel biomaterials for tissue regeneration.

Successful tissue regeneration requires a scaffold with tailorable biodegradability, tissue-like mechanical properties, structural similarity to extracellular matrix (ECM), relevant bioactivity, and cytocompatibility. In recent years, injectable hydrogels have spurred increasing attention in translational medicine as a result of their tunable physicochemical properties in response to the surrounding environment. Furthermore, they have the potential to be implanted via minimally invasive procedures while enabling deep penetration, which is considered a feasible alternative to traditional open surgical procedures. However, polymeric hydrogels may lack sufficient stability and bioactivity in physiological environments. Composite hydrogels containing bioactive glass (BG) particulates, synergistically combining the advantages of their constituents, have emerged as multifunctional biomaterials with tailored mechanical properties and biological functionalities. This review paper highlights the recent advances in injectable composite hydrogel systems based on biodegradable polymers and BGs. The influence of BG particle geometry, composition, and concentration on gel formation, rheological and mechanical behavior as well as hydration and biodegradation of injectable hydrogels have been discussed. The applications of these composite hydrogels in tissue engineering are additionally described, with particular attention to bone and skin. Finally, the prospects and current challenges in the development of desirable injectable bioactive hydrogels for tissue regeneration are discussed to outline a roadmap for future research. STATEMENT OF SIGNIFICANCE: Developing a biomaterial that can be readily available for surgery, implantable via minimally invasive procedures, and be able to effectively stimulate tissue regeneration is one of the grand challenges in modern biomedicine. This review summarizes the state-of-the-art of injectable bioactive glass-polymer composite hydrogels to address several challenges in bone and soft tissue repair. The current limitations and the latest evolutions of these composite biomaterials are critically examined, and the roles of design parameters, such as composition, concentration, and size of the bioactive phase, and polymer-glass interactions on the rheological, mechanical, biological, and overall functional performance of hydrogels are detailed. Existing results and new horizons are discussed to provide a state-of-the-art review that may be useful for both experienced and early-stage researchers in the biomaterials community.