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Contains fulltext : 291335.pdf (Publisher’s version ) (Open Access) Biomaterials with the ability to self-heal and recover their structural integrity offer many advantages for applications in biomedicine. The past decade has witnessed the rapid emergence of a new class of self-healing biomaterials commonly termed injectable, or printable in the context of 3D printing. These self-healing injectable biomaterials, mostly hydrogels and other soft condensed matter based on reversible chemistry, are able to temporarily fluidize under shear stress and subsequently recover their original mechanical properties. Self-healing injectable hydrogels offer distinct advantages compared to traditional biomaterials. Most notably, they can be administered in a locally targeted and minimally invasive manner through a narrow syringe without the need for invasive surgery. Their moldability allows for a patient-specific intervention and shows great prospects for personalized medicine. Injected hydrogels can facilitate tissue regeneration in multiple ways owing to their viscoelastic and diffusive nature, ranging from simple mechanical support, spatiotemporally controlled delivery of cells or therapeutics, to local recruitment and modulation of host cells to promote tissue regeneration. Consequently, self-healing injectable hydrogels have been at the forefront of many cutting-edge tissue regeneration strategies. This study provides a critical review of the current state of self-healing injectable hydrogels for tissue regeneration. As key challenges toward further maturation of this exciting research field, we identify (i) the trade-off between the self-healing and injectability of hydrogels vs their physical stability, (ii) the lack of consensus on rheological characterization and quantitative benchmarks for self-healing injectable hydrogels, particularly regarding the capillary flow in syringes, and (iii) practical limitations regarding translation toward therapeutically effective formulations for regeneration of specific tissues. Hence, here we (i) review chemical and physical design strategies for self-healing injectable hydrogels, (ii) provide a practical guide for their rheological analysis, and (iii) showcase their applicability for regeneration of various tissues and 3D printing of complex tissues and organoids.

Immune cells are being engineered to recognize and respond to disease states, acting as a “living drug” when transferred into patients. Therapies based on engineered immune cells are now a clinical reality, with multiple engineered T cell therapies approved for treatment of hematologic malignancies. Ongoing preclinical and clinical studies are testing diverse strategies to modify the fate and function of immune cells for applications in cancer, infectious disease, and beyond. Here, we discuss current progress in treating human disease with immune cell therapeutics, emerging strategies for immune cell engineering, and challenges facing the field, with a particular emphasis on the treatment of cancer, where the most effort has been applied to date.

Tumor and immune cells interact through a variety of cell-surface proteins that can either restrain or promote tumor progression. The impacts of cytotoxic chemotherapy dose and delivery route on this interaction profile remain incompletely understood, and could support the development of more effective combination therapies for cancer treatment.Here, we found that exposure to the anthracycline doxorubicin altered the expression of numerous immune-interacting markers (MHC-I, PD-L1, PD-L2, CD47, Fas, and calreticulin) on live melanoma, breast cancer, and leukemia cells in a dose-dependent mannerTogether, these results illustrate how standard-of-care chemotherapy, when administered in various manners, can lead to distinct expression of immunogenic markers on cancer cells. These findings may inform development of chemo-immunotherapy combinations for cancer treatment.The online version contains supplementary material available at 10.1007/s12195-022-00742-y.

Skin injuries across the body continue to disrupt everyday life for millions of patients and result in prolonged hospital stays, infection, and death. Advances in wound healing devices have improved clinical practice but have mainly focused on treating macroscale healing versus underlying microscale pathophysiology. Consensus is lacking on optimal treatment strategies using a spectrum of wound healing products, which has motivated the design of new therapies. We summarize advances in the development of novel drug, biologic products, and biomaterial therapies for wound healing for marketed therapies and those in clinical trials. We also share perspectives for successful and accelerated translation of novel integrated therapies for wound healing.

The extracellular matrix (ECM) mechanical properties regulate key cellular processes in tissue development and regeneration. The majority of scientific investigation has focused on ECM elasticity as the primary mechanical regulator of cell and tissue behavior. However, all living tissues are viscoelastic, exhibiting both solid- and liquid-like mechanical behavior. Despite increasing evidence regarding the role of ECM viscoelasticity in directing cellular behavior, this aspect is still largely overlooked in the design of biomaterials for tissue regeneration. Recently, with the emergence of various bottom-up material design strategies, new approaches can deliver unprecedented control over biomaterial properties at multiple length scales, thus enabling the design of viscoelastic biomaterials that mimic various aspects of the native tissue ECM microenvironment. This review describes key considerations for the design of viscoelastic biomaterials for tissue regeneration. We provide an overview of the role of matrix viscoelasticity in directing cell behavior toward regenerative outcomes, highlight recent strategies utilizing viscoelastic hydrogels for regenerative therapies, and outline remaining challenges, potential solutions, and emerging applications for viscoelastic biomaterials in tissue engineering and regenerative medicine. IMPACT STATEMENT: All living tissues are viscoelastic. As we design viscoelastic biomaterials for tissue engineering and regenerative medicine, we must understand the effect of matrix viscoelasticity on in vitro cell behavior and in vivo regenerative outcomes. Engineering the next generation of biomaterials with tunable viscoelasticity to direct cell and tissue behavior will contribute to the development of in vitro tissue models and in vivo regenerative therapies to address unmet clinical needs.

Most cancer vaccines target peptide antigens, necessitating personalization owing to the vast inter-individual diversity in major histocompatibility complex (MHC) molecules that present peptides to T cells. Furthermore, tumours frequently escape T cell-mediated immunity through mechanisms that interfere with peptide presentation

Nanoparticle-based delivery of therapeutics to the brain has had limited clinical impact due to challenges crossing the blood-brain barrier (BBB). Certain cells, such as monocytes, possess the ability to migrate across the BBB, making them attractive candidates for cell-based brain delivery strategies. In this work, we explore nanoparticle design parameters that impact both monocyte association and monocyte-mediated BBB transport. We use electrohydrodynamic jetting to prepare nanoparticles of varying sizes, compositions, and elasticity to address their impact on uptake by THP-1 monocytes and permeation across the BBB. An

Aging is the largest risk factor for Achilles tendon associated disorders and rupture. Although Achilles tendon macroscale elastic properties are suggested to decline with aging, less is known about the effect of maturity and aging on multiscale viscoelastic properties and their effect on tendon cell behavior. Here, we show dose dependent changes in native multiscale tendon mechanical and structural properties and uncover several nanoindentation properties predicted by tensile mechanics and echogenicity. Alginate hydrogel systems designed to mimic juvenile tendon microscale mechanics revealed that stiffness and viscoelasticity affected Achilles tendon cell aspect ratio and proliferation during aging. This knowledge provides further evidence for the negative impact of maturity and aging on tendon and begins to elucidate how viscoelasticity can control tendon derived cell morphology and expansion., Statement of significance, Aging is the largest risk factor for Achilles tendon associated disorders and rupture. Although Achilles tendon macroscale elastic properties are suggested to decline with aging, less is known about the effect of maturity and aging on multiscale viscoelastic properties and their effect on tendon cell behavior. Here, we show dose dependent changes in native multiscale tendon mechanical and structural properties and uncover several nanoindentation properties predicted by tensile mechanics and echogenicity. Alginate hydrogel systems designed to mimic juvenile tendon microscale mechanics revealed that stiffness and viscoelasticity affected Achilles tendon cell spreading and proliferation during aging. This knowledge provides further evidence for the negative impact of maturity and aging on tendon and begins to elucidate how viscoelasticity can control tendon derived cell morphology and expansion. (c) 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

We demonstrate that a poly(lactide-co-glycolide) (PLG) cancer vaccine can be used in combination with immune checkpoint antibodies, anti–CTLA-4 or anti–PD-1, to enhance cytotoxic T-cell (CTL) activity and induce the regression of solid B16 tumors in mice. Combination therapy obviated the need for vaccine boosting and significantly skewed intratumoral reactions toward CTL activity, resulting in the regression of B16 tumors up to 50 mm2 in size and 75% survival rates. These data suggest that combining material-based cancer vaccines with checkpoint antibodies has the potential to mediate tumor regression in humans. Cancer Immunol Res; 4(2); 95–100. ©2015 AACR.

Figure S1 - Treatment of tumor bearing mice with anti-CTLA-4 and Anti-PD1 antibodies. Figure S2 - The effects of stopping antibody treatment after PLG vaccination on tumor growth. Figure S3 - The ratio of CD3(+)CD8(+) T cells to CD3(+)FoxP3(+) T regulatory cells isolated from the B16 tumors of untreated mice (Control) and mice treated with PLG vaccines alone (Vax) or in combination with anti-PD-1 (+PD-1) and anti-CTLA-4 (+CTLA-4) antibodies. Figure S4 - Combining multiple checkpoint blockades with PLG cancer vaccines. Figure S5 - Effector and regulatory T cell activity in lymph node that drains vaccine site.

PDF file - 129KB, Activated dendritic cell numbers at the vaccine implant site (S1); The kinetics of activated dendritic cell generation at vaccine site (S2); IFN-a production at vaccine sites (S3); TNF-a production at vaccine sites (S4); Prophylactic B16-F10 vaccination in MyD88 and TRIF KO models (S5); Vaccine induced T cell recruitment (S6); Comparison of IL-12 production at vaccine sites in wild type and cytotoxic T cell knockout mice (S7); Comparison of IFN-y production at vaccine sites in wild type and cytotoxic T cell knockout mice (S8); Comparison of dendritic cell generation at vaccine sites in wild type and CD8 dendritic cell knockout mice (S9); Comparison of IL-6 production at the vaccine site in wild type and CD8 dendritic cell knockouts (S10); Comparison of G-CSF production at the vaccine site in wild type and CD8 dendritic cell knockout mice (S11).

PDF file - 237KB, Vaccine induction of inflammatory cytokine production at the vaccine site (S1); The correlation between local cytokine concentration and survival outcome in vaccinated mice (S2).

The innate cellular and molecular components required to mediate effective vaccination against weak tumor-associated antigens remain unclear. In this study, we used polymeric cancer vaccines incorporating different classes of adjuvants to induce tumor protection, to identify dendritic cell (DC) subsets and cytokines critical to this efficacy. Three-dimensional, porous polymer matrices loaded with tumor lysates and presenting distinct combinations of granulocyte macrophage colony-stimulating factor (GM-CSF) and various Toll-like receptor (TLR) agonists affected 70% to 90% prophylactic tumor protection in B16-F10 melanoma models. In aggressive, therapeutic B16 models, the vaccine systems incorporating GM-CSF in combination with P(I:C) or CpG-ODN induced the complete regression of solid tumors (≤40 mm2), resulting in 33% long-term survival. Regression analysis revealed that the numbers of vaccine-resident CD8(+) DCs, plasmacytoid DCs (pDC), along with local interleukin (IL)-12, and granulocyte colony-stimulating factor (G-CSF) concentrations correlated strongly to vaccine efficacy regardless of adjuvant type. Furthermore, vaccine studies in Batf3−/− mice revealed that CD8(+) DCs are required to affect tumor protection, as vaccines in these mice were deficient in cytotoxic T lymphocytes priming and IL-12 induction in comparison with wild-type. These studies broadly demonstrate that three-dimensional polymeric vaccines provide a potent platform for prophylactic and therapeutic protection, and can be used as a tool to identify critical components of a desired immune response. Specifically, these results suggest that CD8(+) DCs, pDCs, IL-12, and G-CSF play important roles in priming effective antitumor responses with these vaccines. Cancer Res; 74(6); 1670–81. ©2014 AACR.

Hydrogels that provide mechanical support and sustainably release therapeutics have been used to treat tendon injuries. However, most hydrogels are insufficiently tough, release drugs in bursts, and require cell infiltration or suturing to integrate with surrounding tissue. Here we report that a hydrogel serving as a high-capacity drug depot and combining a dissipative tough matrix on one side and a chitosan adhesive surface on the other side supports tendon gliding and strong adhesion (larger than 1,000 J msup-2/sup) to tendon on opposite surfaces of the hydrogel, as we show with porcine and human tendon preparations during cyclic-friction loadings. The hydrogel is biocompatible, strongly adheres to patellar, supraspinatus and Achilles tendons of live rats, boosted healing and reduced scar formation in a rat model of Achilles-tendon rupture, and sustainably released the corticosteroid triamcinolone acetonide in a rat model of patellar tendon injury, reducing inflammation, modulating chemokine secretion, recruiting tendon stem and progenitor cells, and promoting macrophage polarization to the M2 phenotype. Hydrogels with 'Janus' surfaces and sustained-drug-release functionality could be designed for a range of biomedical applications.

Face mask usage is one of the most effective ways to limit SARS-CoV-2 transmission, but a mask is only useful if user compliance is high. Through anonymous surveys (n = 679), it was shown that mask discomfort is the primary source of noncompliance in mask wearing. Further, through these surveys, three critical predicting variables that dictate mask comfort were identified: air resistance, water vapor permeability, and face temperature change. To validate these predicting variables in a physiological context, experiments (n = 9) were performed to measure the respiratory rate and change in face temperature while wearing different types of three commonly used masks. Finally, using values of these predicting variables from experiments and the literature, and surveys asking users to rate the comfort of various masks, three machine learning algorithms were trained and tested to generate overall comfort scores for those masks. Although all three models performed with an accuracy of approximately 70%, the multiple linear regression model provides a simple analytical expression to predict the comfort scores for common face masks provided the input predicting variables. As face mask usage is crucial during the COVID-19 pandemic, the goal of this quantitative framework to predict mask comfort is hoped to improve user experience and prevent discomfort-induced noncompliance.

Multielectrode arrays are fabricated from thin films of highly conductive and ductile metals, which cannot mimic the natural environment of biological tissues. These properties limit the conformability of the electrode to the underlying target tissue and present challenges in developing seamless interfaces. By introducing porous, hydrogel materials that are embedded with metal additives, highly conductive hydrogels can be formed. Tuning the hydrogel composition, % volume and aspect ratio of different additive(s), and the processing conditions of these composite materials can alter the mechanical and electrical properties. The resulting materials have a high surface area and can be used as biomaterial scaffolds to support the growth of macrophages for 5 days. Further optimization can enable the use of the materials for the electrodes in implantable arrays, or as living electrode platforms, to study and modulate various cellular cultures. These advancements would benefit both in vivo and in vitro applications of tissue engineering.

Adoptive T cell transfer (ACT) therapies suffer from a number of limitations (e.g., poor control of solid tumors), and while combining ACT with cytokine therapy can enhance effectiveness, this also results in significant side effects. Here, we describe a nanotechnology approach to improve the efficacy of ACT therapies by metabolically labeling T cells with unnatural sugar nanoparticles, allowing direct conjugation of antitumor cytokines onto the T cell surface during the manufacturing process. This allows local, concentrated activity of otherwise toxic cytokines. This approach increases T cell infiltration into solid tumors, activates the host immune system toward a Type 1 response, encourages antigen spreading, and improves control of aggressive solid tumors and achieves complete blood cancer regression with otherwise noncurative doses of CAR-T cells. Overall, this method provides an effective and easily integrated approach to the current ACT manufacturing process to increase efficacy in various settings.

Lymph nodes (LNs) dynamically expand in response to immunization, but the relationship between LN expansion and the accompanying adaptive immune response is unclear. Here, we first characterized the LN response across time and length scales to vaccines of distinct strengths. High-frequency ultrasound revealed that a bolus ‘weak’ vaccine induced a short-lived, 2-fold volume expansion, while a biomaterial-based ‘strong’ vaccine elicited an ∼7-fold LN expansion, which was maintained several weeks after vaccination. This latter expansion was associated with altered matrix and mechanical properties of the LN microarchitecture. Strong vaccination resulted in massive immune and stromal cell engagement, dependent on antigen presence in the vaccine, and conventional dendritic cells and inflammatory monocytes upregulated genes involved in antigen presentation and LN enlargement. The degree of LN expansion following therapeutic cancer vaccination strongly correlated with vaccine efficacy, even 100 days post-vaccination, and direct manipulation of LN expansion demonstrated a causative role in immunization outcomes.

Adoptive T cell therapy provides the T cell pool needed for immediate tumor debulking, but the infused T cells generally have a narrow repertoire for antigen recognition and limited ability for long-term protection. Here, we present a biomaterial platform that enhances adoptive T cell therapy by synergistically engaging the host immune system via in-situ antigen-free vaccination. T cells alone loaded into these localized cell depots provided significantly better control of subcutaneous B16-F10 tumors than T cells delivered through direct peritumoral injection or intravenous infusion. The anti-tumor response was significantly enhanced when T cell delivery was combined with biomaterial-driven accumulation and activation of host immune cells, as this prolonged the activation state of the delivered T cells, minimized host T cell exhaustion, and enabled long-term tumor control. This integrated approach provides both immediate tumor debulking and long-term protection against solid tumors, including against tumor antigen escape.

Most bacterial vaccines work for a subset of bacterial strains or require the modification of the antigen or isolation of the pathogen before vaccine development. Here we report injectable biomaterial vaccines that trigger potent humoral and T-cell responses to bacterial antigens by recruiting, reprogramming and releasing dendritic cells. The vaccines are assembled from regulatorily approved products and consist of a scaffold with absorbed granulocyte-macrophage colony-stimulating factor and CpG-rich oligonucleotides incorporating superparamagnetic microbeads coated with the broad-spectrum opsonin Fc-mannose-binding lectin for the magnetic capture of pathogen-associated molecular patterns from inactivated bacterial-cell-wall lysates. The vaccines protect mice against skin infection with methicillin-resistant Staphylococcus aureus, mice and pigs against septic shock from a lethal Escherichia coli challenge and, when loaded with pathogen-associated molecular patterns isolated from infected animals, uninfected animals against a challenge with different E. coli serotypes. The strong immunogenicity and low incidence of adverse events, a modular manufacturing process, and the use of components compatible with current good manufacturing practice could make this vaccine technology suitable for responding to bacterial pandemics and biothreats.

Cancer nanomedicines were initially envisioned as magic bullets, travelling through the circulation to target tumours while sparing healthy tissues the toxicity of classic chemotherapy. While a limited number of nanomedicine therapies have resulted, the disappointing news is that major obstacles were overlooked in the nanoparticle's journey. However, some of these challenges may be turned into opportunities. Here, we discuss biological barriers to cancer nanomedicines and elaborate on two directions that the field is currently exploring to meet its initial expectations. The first strategy entails re-engineering cancer nanomedicines to prevent undesired interactions en route to the tumour. The second aims instead to leverage these obstacles into out-of-the-box diagnostic and therapeutic applications of nanomedicines, for cancer and beyond. Both paths require, among other developments, a deeper understanding of nano-bio interactions. We offer a forward look at how classic cancer nanomedicine may overcome its limitations while contributing to other areas of research.

Adipocytes are key regulators of human metabolism, and their dysfunction in insulin signaling is central to metabolic diseases including type II diabetes mellitus (T2D). However, the progression of insulin resistance into T2D is still poorly understood. This limited understanding is due, in part, to the dearth of suitable models of insulin signaling in human adipocytes. Traditionally, adipocyte models fail to recapitulate in vivo insulin signaling, possibly due to exposure to supraphysiological nutrient and hormone conditions. We developed a protocol for human pluripotent stem cell–derived adipocytes that uses physiological nutrient conditions to produce a potent insulin response comparable to in vivo adipocytes. After systematic optimization, this protocol allows robust insulin-stimulated glucose uptake and transcriptional insulin response. Furthermore, exposure of sensitized adipocytes to physiological hyperinsulinemia dampens insulin-stimulated glucose uptake and dysregulates insulin-responsive transcription. Overall, our methodology provides a novel platform for the mechanistic study of insulin signaling and resistance using human pluripotent stem cell–derived adipocytes.

Diseases of immunity, including autoimmune diseases such as multiple sclerosis, transplantation graft rejection, allergy, and asthma, are prevalent and increasing in prevalence. They contribute to significant morbidity and mortality; however, few if any curative therapies exist, and those that are available lack either potency or specificity. Dendritic cells (DCs) are sentinels of the immune system that connect the innate and adaptive immune system and are critical regulators of both immunity and tolerance. We posited that the tolerogenic potential of DC could be harnessed to develop more specific and potent therapies for diseases of immunity by delivering autoantigen to a sufficient number of tolerogenic DCs in situ that could then inhibit pathogenic effector T cell responses. Specifically, we hypothesized that the steroid dexamethasone covalently coupled to a peptide antigen could be processed by DCs, induce tolerogenic DCs, and attenuate antigen-specific pathogenic T cell responses. To test this hypothesis, we synthesized a series of dexamethasone-peptide immunoconjugates by standard solid-phase peptide synthesis. The antigenic portion of the immunoconjugate could be presented by DCs, and the immunoconjugate induced a tolerogenic phenotype in DCs that then inhibited antigen-specific T cell proliferation in vitro. When the immunoconjugate was administered prophylactically in the murine experimental autoimmune encephalomyelitis model of multiple sclerosis, disease was attenuated compared to dexamethasone and peptide delivered as uncoupled components. Together, this work demonstrates the utility of immunoconjugates for inducing tolerance while establishing the foundation for future studies exploring methods to enrich and target DCs for tolerogenic therapies.

Metabolic glycoengineering with unnatural sugars provides a powerful tool to label cell membranes with chemical tags for subsequent targeted conjugation of molecular cargos via efficient chemistries. This technology has been widely explored for cancer labelling and targeting. However, as this metabolic labelling process can occur in both cancerous and normal cells, cancer-selective labelling needs to be achieved to develop cancer-targeted therapies. Unnatural sugars can be either rationally designed to enable preferential labelling of cancer cells, or specifically delivered to cancerous tissues. In this Review Article, we will discuss the progress to date in design and delivery of unnatural sugars for metabolic labelling of tumour cells and subsequent development of tumour-targeted therapy. Metabolic cell labelling for cancer immunotherapy will also be discussed. Finally, we will provide a perspective on future directions of metabolic labelling of cancer and immune cells for the development of potent, clinically translatable cancer therapies.

Mammalian cell morphology has been linked to the viscoelastic properties of the adhesion substrate, which is particularly relevant in biological processes such as wound repair and embryonic development where cell spreading and migration are critical. Plastic deformation, degradation, and relaxation of stress are typically coupled in biomaterial systems used to explore these effects, making it unclear which variable drives cell behavior. Here we present a nondegradable polymer architecture that specifically decouples irreversible creep from stress relaxation and modulus. We demonstrate that network plasticity independently controls mesenchymal stem cell spreading through a biphasic relationship dependent on cell-intrinsic forces, and this relationship can be shifted by inhibiting actomyosin contractility. Kinetic Monte Carlo simulations also show strong correlation with experimental cell spreading data as a function of the extracellular matrix (ECM) plasticity. Furthermore, plasticity regulates many ECM adhesion and remodeling genes. Altogether, these findings confirm a key role for matrix plasticity in stem cell biophysics, and we anticipate this will have ramifications in the design of biomaterials to enhance therapeutic applications of stem cells.

Hydrogels with patterned biophysical and biochemical properties have found increasing attention in the biomaterials community. In this work, we explore alginate-based materials with two orthogonal crosslinking mechanisms: the spontaneous Diels-Alder reaction and the ultraviolet light-initiated thiol-ene reaction. Combining these mechanisms in one material and spatially restricting the location of the latter using photomasks, enables the formation of dual-crosslinked hydrogels with patterns in stiffness, biomolecule presentation and degradation, granting local control over cell behavior. Patterns in stiffness are characterized morphologically by confocal microscopy and mechanically by uniaxial compression and microindentation measurement. Mouse embryonic fibroblasts seeded on stiffness-patterned substrates attach preferably and attain a spread morphology on stiff compared to soft regions. Human mesenchymal stem cells demonstrate preferential adipogenic differentiation on soft surfaces and osteogenic differentiation on stiff surfaces. Patterns in biomolecule presentation reveal favored attachment of mouse pre-osteoblasts on stripe regions, where thiolated cell-adhesive biomolecules have been coupled. Patterns in degradation are visualized by microindentation measurement following collagenase exposure. Patterned tissue infiltration into degradable regions on the surface is discernible in n=5/12 samples, when these materials are implanted subcutaneously into the backs of mice. Taken together, these results demonstrate that our hydrogel system with patterns in biophysical and biochemical properties enables the study of how environmental cues affect multiple cell behaviors in vitro and could be applied to guide endogenous tissue growth in diverse healing scenarios in vivo. Statement of Significance Hydrogels with patterns in biophysical and biochemical properties have been explored in the biomaterials community in order to spatially control or guide cell behavior. In our alginate-based system, we demonstrate the effect of local substrate stiffness and biomolecule presentation on the in vitro cell attachment, morphology, migration and differentiation behavior of two different mouse cell lines and human primary cells. Additionally, the effect of degradation patterns on the in vivo tissue infiltration is analyzed following subcutaneous implantation into a mouse model. The achievement of patterned tissue infiltration following the hydrogel template represents an important step towards guiding endogenous healing responses, thus inviting application in various tissue engineering contexts.

Substantial research over the past two decades has established that extracellular matrix (ECM) elasticity, or stiffness, affects fundamental cellular processes, including spreading, growth, proliferation, migration, differentiation and organoid formation. Linearly elastic polyacrylamide hydrogels and polydimethylsiloxane (PDMS) elastomers coated with ECM proteins are widely used to assess the role of stiffness, and results from such experiments are often assumed to reproduce the effect of the mechanical environment experienced by cells in vivo. However, tissues and ECMs are not linearly elastic materials-they exhibit far more complex mechanical behaviours, including viscoelasticity (a time-dependent response to loading or deformation), as well as mechanical plasticity and nonlinear elasticity. Here we review the complex mechanical behaviours of tissues and ECMs, discuss the effect of ECM viscoelasticity on cells, and describe the potential use of viscoelastic biomaterials in regenerative medicine. Recent work has revealed that matrix viscoelasticity regulates these same fundamental cell processes, and can promote behaviours that are not observed with elastic hydrogels in both two- and three-dimensional culture microenvironments. These findings have provided insights into cell-matrix interactions and how these interactions differentially modulate mechano-sensitive molecular pathways in cells. Moreover, these results suggest design guidelines for the next generation of biomaterials, with the goal of matching tissue and ECM mechanics for in vitro tissue models and applications in regenerative medicine.

Background Periodontal disease results from the pathogenic interactions between the tissue, immune system, and microbiota; however, standard therapy fails to address the cellular mechanism underlying the chronic inflammation. Dendritic cells (DC) are key regulators of T cell fate, and biomaterials that recruit and program DC locally can direct T cell effector responses. We hypothesized that a biomaterial that recruited and programmed DC toward a tolerogenic phenotype could enrich regulatory T cells within periodontal tissue, with the eventual goal of attenuating T cell mediated pathology. Methods The interaction of previously identified factors that could induce tolerance, granulocyte-macrophage colony stimulating factor (GM-CSF) and thymic stromal lymphopoietin (TSLP), with the periodontitis network was confirmed in silico. The effect of the cytokines on DC migration was explored in vitro using time-lapse imaging. Finally, regulatory T cell enrichment in the dermis and periodontal tissue in response to alginate hydrogels delivering TSLP and GM-CSF was examinedin vivo in mice using immunohistochemistry and live-animal imaging. Results The GM-CSF and TSLP interactome connects to the periodontitis network. GM-CSF enhances DC migration in vitro. An intradermal injection of an alginate hydrogel releasing GM-CSF enhanced DC numbers and the addition of TSLP enriched FOXP3+ regulatory T cells locally. Injection of a hydrogel with GM-CSF and TSLP into the periodontal tissue in mice increased DC and FOXP3+ cell numbers in the tissue, FOXP3+ cells in the lymph node, and IL-10 in the tissue. Conclusion Local biomaterial-mediated delivery of GM-CSF and TSLP can enrich DC and FOXP3+ cells and holds promise for treating the pathologic inflammation of periodontal disease.