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Cell-matrix interactions in 3D environments significantly differ from those in 2D cultures. As such, mechanisms of mechanotransduction in 2D cultures are not necessarily applicable to cell-encapsulating hydrogels that resemble features of tissue architecture. Accordingly, the characterization of molecular pathways in 3D matrices is expected to uncover insights into how cells respond to their mechanical environment in physiological contexts, and potentially also inform hydrogel-based strategies in cell therapies. In this study, a bone marrow-mimetic hydrogel was employed to systematically investigate the stiffness-responsive transcriptome of mesenchymal stromal cells. High matrix rigidity impeded integrin-collagen adhesion, resulting in changes in cell morphology characterized by a contractile network of actin proximal to the cell membrane. This resulted in a suppression of extracellular matrix-regulatory genes involved in the remodeling of collagen fibrils, as well as the upregulation of secreted immunomodulatory factors. Moreover, an investigation of long noncoding RNAs revealed that the cytoskeleton regulator RNA (CYTOR) contributes to these 3D stiffness-driven changes in gene expression. Knockdown of CYTOR using antisense oligonucleotides enhanced the expression of numerous mechanoresponsive cytokines and chemokines to levels exceeding those achievable by modulating matrix stiffness alone. Taken together, our findings further our understanding of mechanisms of mechanotransduction that are distinct from canonical mechanotransductive pathways observed in 2D cultures.
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Matriz Extracelular , Mecanotransducción Celular , Células Madre Mesenquimatosas , ARN Largo no Codificante , Humanos , Células Madre Mesenquimatosas/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Matriz Extracelular/metabolismo , Hidrogeles/química , Regulación de la Expresión Génica , Colágeno/metabolismo , Células Cultivadas , Inmunomodulación/genéticaRESUMEN
BACKGROUND: Current dressing materials cannot secure a cell survival-promoting wound environment for stem cell delivery due to insufficient assimilation to skin motion. The authors developed a novel motion-accommodating dual-layer hydrogel dressing for stem cell delivery into such wounds. METHODS: Dorsal hand skin movement was evaluated to determine the potential range of deformation for a dressing. The outer hydrogel (OH) was fabricated with an alginate-acrylamide double-network hydrogel with a covalently cross-linked elastomer coat. The tough adhesive consisted of a chitosan-based bridging polymer and coupling reagents. OH material properties and adhesiveness on porcine skin were measured. An oxidized alginate-based inner hydrogel (IH) containing human adipose-derived stem cells (ASCs) was evaluated for cell-supporting and cell-releasing properties. The OH's function as a secondary dressing, and dual-layer hydrogel cell delivery potential in wounds were assessed in a rodent model. RESULTS: The dual-layer hydrogel consisted of OH and IH. The OH target range of deformation was up to 25% strain. The OH adhered to porcine skin, and showed significantly higher adhesion energy than common secondary dressings and endured 900 flexion-extension cycles without detachment. OH showed a similar moisture vapor transmission rate as moisture-retentive dressings. IH maintained embedded cell survival for three days with significant cell release on the contacting surface. OH showed less fibrotic wound healing than other secondary dressings in vivo. The dual-layer hydrogel successfully delivered ASCs into open wounds of nude mice (13 ± 3 cells/HPF). CONCLUSIONS: The novel dual-layer hydrogel can accommodate patient movement and deliver ASCs into the wound bed by securing the wound microenvironment.
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Tejido Adiposo , Vendajes , Células Madre , Cicatrización de Heridas , Animales , Humanos , Células Madre/citología , Porcinos , Tejido Adiposo/citología , Cicatrización de Heridas/efectos de los fármacos , Trasplante de Células Madre/métodos , Hidrogeles/química , Hidrogeles/farmacología , Ratones , PielRESUMEN
The efficacy of adoptive T-cell therapies based on chimaeric antigen receptors (CARs) is limited by the poor proliferation and persistence of the engineered T cells. Here we show that a subcutaneously injected biodegradable scaffold that facilitates the infiltration and egress of specific T-cell subpopulations, which forms a microenvironment mimicking features of physiological T-cell activation, enhances the antitumour activity of pre-administered CAR-T cells. CAR-T-cell expansion, differentiation and cytotoxicity were driven by the scaffold's incorporation of co-stimulatory bound ligands and soluble molecules, and depended on the types of co-stimulatory molecules and the context in which they were presented. In mice with aggressive lymphoma, a single, local injection of the scaffold following non-curative CAR-T-cell dosing led to more persistent memory-like T cells and extended animal survival. Injectable biomaterials with optimized ligand presentation may boost the therapeutic performance of CAR-T-cell therapies.
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Increasing the potency, quality, and durability of vaccines represents a major public health challenge. A critical parameter that shapes vaccine immunity is the spatiotemporal context in which immune cells interact with antigen and adjuvant. While various material-based strategies demonstrate that extended antigen release enhances both cellular and humoral immunity, the effect of adjuvant kinetics on vaccine-mediated immunity remains incompletely understood. Here, a previously characterized mesoporous silica rod (MPS) biomaterial vaccine is used to develop a facile, electrostatics-driven approach to tune in vivo kinetics of the TLR9 agonist cytosine phosphoguanosine oligodeoxynucleotide (CpG). It is demonstrated that rapid release of CpG from MPS vaccines, mediated by alterations in MPS chemistry that tune surface charge, generates potent cytotoxic T cell responses and robust, T helper type 1 (Th1)-skewed IgG2a/c antibody titers. Immunophenotyping of lymphoid organs after MPS vaccination with slow or fast CpG release kinetics suggests that differential engagement of migratory dendritic cells and natural killer cells may contribute to the more potent responses observed with rapid adjuvant release. Taken together, these findings suggest that vaccine approaches that pair sustained release of antigen with rapid release of adjuvants with similar characteristics to CpG may drive particularly potent Th1 responses.
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Following immunization, lymph nodes dynamically expand and contract. The mechanical and cellular changes enabling the early-stage expansion of lymph nodes have been characterized, yet the durability of such responses and their implications for adaptive immunity and vaccine efficacy are unknown. Here, by leveraging high-frequency ultrasound imaging of the lymph nodes of mice, we report more potent and persistent lymph-node expansion for animals immunized with a mesoporous silica vaccine incorporating a model antigen than for animals given bolus immunization or standard vaccine formulations such as alum, and that durable and robust lymph-node expansion was associated with vaccine efficacy and adaptive immunity for 100 days post-vaccination in a mouse model of melanoma. Immunization altered the mechanical and extracellular-matrix properties of the lymph nodes, drove antigen-dependent proliferation of immune and stromal cells, and altered the transcriptional features of dendritic cells and inflammatory monocytes. Strategies that robustly maintain lymph-node expansion may result in enhanced vaccination outcomes.
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Wounds often necessitate the use of instructive biomaterials to facilitate effective healing. Yet, consistently filling the wound and retaining the material in place presents notable challenges. Here, we develop a new class of injectable tissue adhesives by leveraging the dynamic crosslinking chemistry of Schiff base reactions. These adhesives demonstrate outstanding mechanical properties, especially in regard to stretchability and self-healing capacity, and biodegradability. Furthermore, they also form robust adhesion to biological tissues. Their therapeutic potential was evaluated in a rodent model of volumetric muscle loss (VML). Ultrasound imaging confirmed that the adhesives remained within the wound site, effectively filled the void, and degraded at a rate comparable to the healing process. Histological analysis indicated that the adhesives facilitated muscle fiber and blood vessel formation, and induced anti-inflammatory macrophages. Notably, the injured muscles of mice treated with the adhesives displayed increased weight and higher force generation than the control groups. This approach to adhesive design paves the way for the next generation of medical adhesives in tissue repair.
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Regeneración , Adhesivos Tisulares , Cicatrización de Heridas , Animales , Adhesivos Tisulares/química , Adhesivos Tisulares/farmacología , Cicatrización de Heridas/efectos de los fármacos , Regeneración/efectos de los fármacos , Ratones , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/lesiones , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Ratones Endogámicos C57BL , MasculinoRESUMEN
Artificial antigen-presenting cells (aAPCs) are currently used to manufacture T cells for adoptive therapy in cancer treatment, but a readily tunable and modular system can enable both rapid T cell expansion and control over T cell phenotype. Here, it is shown that microgels with tailored surface biochemical properties can serve as aAPCs to mediate T cell activation and expansion. Surface functionalization of microgels is achieved via layer-by-layer coating using oppositely charged polymers, forming a thin but dense polymer layer on the surface. This facile and versatile approach is compatible with a variety of coating polymers and allows efficient and flexible surface-specific conjugation of defined peptides or proteins. The authors demonstrate that tethering appropriate stimulatory ligands on the microgel surface efficiently activates T cells for polyclonal and antigen-specific expansion. The expansion, phenotype, and functional outcome of primary mouse and human T cells can be regulated by modulating the concentration, ratio, and distribution of stimulatory ligands presented on microgel surfaces as well as the stiffness and viscoelasticity of the microgels.
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Células Presentadoras de Antígenos , Microgeles , Propiedades de Superficie , Linfocitos T , Animales , Células Presentadoras de Antígenos/inmunología , Linfocitos T/citología , Linfocitos T/metabolismo , Humanos , Microgeles/química , Ratones , Proliferación Celular/efectos de los fármacos , Activación de Linfocitos , Polímeros/químicaRESUMEN
Multivalent presentation of ligands often enhances receptor activation and downstream signalling. DNA origami offers a precise nanoscale spacing of ligands, a potentially useful feature for therapeutic nanoparticles. Here we use a square-block DNA origami platform to explore the importance of the spacing of CpG oligonucleotides. CpG engages Toll-like receptors and therefore acts to activate dendritic cells. Through in vitro cell culture studies and in vivo tumour treatment models, we demonstrate that square blocks induce Th1 immune polarization when CpG is spaced at 3.5 nm. We observe that this DNA origami vaccine enhances DC activation, antigen cross-presentation, CD8 T-cell activation, Th1-polarized CD4 activation and natural-killer-cell activation. The vaccine also effectively synergizes with anti-PD-L1 for improved cancer immunotherapy in melanoma and lymphoma models and induces long-term T-cell memory. Our results suggest that DNA origami may serve as a platform for controlling adjuvant spacing and co-delivering antigens in vaccines.
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Vacunas contra el Cáncer , Oligodesoxirribonucleótidos , Animales , Vacunas contra el Cáncer/química , Vacunas contra el Cáncer/inmunología , Ratones , Oligodesoxirribonucleótidos/química , Oligodesoxirribonucleótidos/farmacología , ADN/química , ADN/inmunología , Células Dendríticas/inmunología , Humanos , Ratones Endogámicos C57BL , Islas de CpG , Vacunas de ADN/química , Vacunas de ADN/inmunología , Vacunas de ADN/farmacología , Linfocitos T CD8-positivos/inmunología , Vacunación/métodos , Línea Celular Tumoral , FemeninoRESUMEN
Complete sequestration of central nervous system tissue and cerebrospinal fluid by the dural membrane is fundamental to maintaining homeostasis and proper organ function, making reconstruction of this layer an essential step during neurosurgery. Primary closure of the dura by suture repair is the current standard, despite facing technical, microenvironmental, and anatomic challenges. Here, we apply a mechanically tough hydrogel paired with a bioadhesive for intraoperative sealing of the dural membrane in rodent, porcine, and human central nervous system tissue. Tensile testing demonstrated that this dural tough adhesive (DTA) exhibited greater toughness with higher maximum stress and stretch compared with commercial sealants in aqueous environments. To evaluate the performance of DTA in the range of intracranial pressure typical of healthy and disease states, ex vivo burst pressure testing was conducted until failure after DTA or commercial sealant application on ex vivo porcine dura with a punch biopsy injury. In contrast to commercial sealants, DTA remained adhered to the porcine dura through increasing pressure up to 300 millimeters of mercury and achieved a greater maximum burst pressure. Feasibility of DTA to repair cerebrospinal fluid leak in a simulated surgical context was evaluated in postmortem human dural tissue. DTA supported effective sutureless repair of the porcine thecal sac in vivo. Biocompatibility and adhesion of DTA was maintained for up to 4 weeks in rodents after implantation. The findings suggest the potential of DTA to augment or perhaps even supplant suture repair and warrant further exploration.
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Hidrogeles , Adhesivos Tisulares , Humanos , Animales , Porcinos , Hidrogeles/farmacología , Pérdida de Líquido Cefalorraquídeo/cirugía , Procedimientos Neuroquirúrgicos , Duramadre/cirugía , Sistema Nervioso Central , Adhesivos Tisulares/farmacologíaRESUMEN
Adoptive T cell immunotherapies, including engineered T cell receptor (eTCR) and chimeric antigen receptor (CAR) T cell immunotherapies, have shown efficacy in treating a subset of hematologic malignancies, exhibit promise in solid tumors, and have many other potential applications, such as in fibrosis, autoimmunity, and regenerative medicine. While immunoengineering has focused on designing biomaterials to present biochemical cues to manipulate T cells ex vivo and in vivo, mechanical cues that regulate their biology have been largely underappreciated. This review highlights the contributions of mechanical force to several receptor-ligand interactions critical to T cell function, with central focus on the TCR-peptide-loaded major histocompatibility complex (pMHC). We then emphasize the role of mechanical forces in (i) allosteric strengthening of the TCR-pMHC interaction in amplifying ligand discrimination during T cell antigen recognition prior to activation and (ii) T cell interactions with the extracellular matrix. We then describe approaches to design eTCRs, CARs, and biomaterials to exploit TCR mechanosensitivity in order to potentiate T cell manufacturing and function in adoptive T cell immunotherapy.
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Medical adhesives are emerging as an important clinical tool as adjuvants for sutures and staples in wound closure and healing and in the achievement of hemostasis. However, clinical adhesives combining cytocompatibility, as well as strong and stable adhesion in physiological conditions, are still in demand. Herein, a mussel-inspired strategy is explored to produce adhesive coacervates using tannic acid (TA) and methacrylate pullulan (PUL-MA). TA|PUL-MA coacervates mainly comprise van der Waals forces and hydrophobic interactions. The methacrylic groups in the PUL backbone increase the number of interactions in the adhesives matrix, resulting in enhanced cohesion and adhesion strength (72.7 Jm-2), compared to the non-methacrylated coacervate. The adhesive properties are kept in physiologic-mimetic solutions (72.8 Jm-2) for 72 h. The photopolymerization of TA|PUL-MA enables the on-demand detachment of the adhesive. The poor cytocompatibility associated with the use of phenolic groups is here circumvented by mixing reactive oxygen species-degrading enzyme in the adhesive coacervate. This addition does not hamper the adhesive character of the materials, nor their anti-microbial or hemostatic properties. This affordable and straightforward methodology, together with the tailorable adhesivity even in wet environments, high cytocompatibility, and anti-bacterial activity, enables foresee TA|PUL-MA as a promising ready-to-use bioadhesive for biomedical applications.
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Antibacterianos , Taninos , Antibacterianos/química , Antibacterianos/farmacología , Taninos/química , Taninos/farmacología , Animales , Polifenoles/química , Polifenoles/farmacología , Adhesivos/química , Adhesivos/farmacología , Glucanos/química , Glucanos/farmacología , Humanos , Ratones , Escherichia coli/efectos de los fármacos , Metacrilatos/química , Polímeros/química , Polímeros/farmacología , Adhesivos Tisulares/química , Adhesivos Tisulares/farmacologíaRESUMEN
Tumour-associated neutrophils can exert antitumour effects but can also assume a pro-tumoural phenotype in the immunosuppressive tumour microenvironment. Here we show that neutrophils can be polarized towards the antitumour phenotype by discoidal polymer micrometric 'patches' that adhere to the neutrophils' surfaces without being internalized. Intravenously administered micropatch-loaded neutrophils accumulated in the spleen and in tumour-draining lymph nodes, and activated splenic natural killer cells and T cells, increasing the accumulation of dendritic cells and natural killer cells. In mice bearing subcutaneous B16F10 tumours or orthotopic 4T1 tumours, intravenous injection of the micropatch-loaded neutrophils led to robust systemic immune responses, a reduction in tumour burden and improvements in survival rates. Micropatch-activated neutrophils combined with the checkpoint inhibitor anti-cytotoxic T-lymphocyte-associated protein 4 resulted in strong inhibition of the growth of B16F10 tumours, and in complete tumour regression in one-third of the treated mice. Micropatch-loaded neutrophils could provide a potent, scalable and drug-free approach for neutrophil-based cancer immunotherapy.
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Inmunoterapia , Ratones Endogámicos C57BL , Neutrófilos , Polímeros , Animales , Neutrófilos/inmunología , Inmunoterapia/métodos , Ratones , Polímeros/química , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacos , Femenino , Ratones Endogámicos BALB C , Melanoma Experimental/inmunología , Melanoma Experimental/terapia , Melanoma Experimental/patología , Neoplasias/inmunología , Neoplasias/terapia , Células Asesinas Naturales/inmunología , HumanosRESUMEN
In calcific aortic valve disease (CAVD), mechanosensitive valvular cells respond to fibrosis- and calcification-induced tissue stiffening, further driving pathophysiology. No pharmacotherapeutics are available to treat CAVD because of the paucity of (i) appropriate experimental models that recapitulate this complex environment and (ii) benchmarking novel engineered aortic valve (AV)-model performance. We established a biomaterial-based CAVD model mimicking the biomechanics of the human AV disease-prone fibrosa layer, three-dimensional (3D)-bioprinted into 96-well arrays. Liquid chromatography-tandem mass spectrometry analyses probed the cellular proteome and vesiculome to compare the 3D-bioprinted model versus traditional 2D monoculture, against human CAVD tissue. The 3D-bioprinted model highly recapitulated the CAVD cellular proteome (94% versus 70% of 2D proteins). Integration of cellular and vesicular datasets identified known and unknown proteins ubiquitous to AV calcification. This study explores how 2D versus 3D-bioengineered systems recapitulate unique aspects of human disease, positions multiomics as a technique for the evaluation of high throughput-based bioengineered model systems, and potentiates future drug discovery.
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Estenosis de la Válvula Aórtica , Válvula Aórtica , Válvula Aórtica/patología , Calcinosis , Humanos , Válvula Aórtica/química , Válvula Aórtica/metabolismo , Proteómica , Proteoma/metabolismo , Estenosis de la Válvula Aórtica/etiología , Estenosis de la Válvula Aórtica/metabolismo , Células CultivadasRESUMEN
Generating strong rapid adhesion between hydrogels has the potential to advance the capabilities of modern medicine and surgery. Current hydrogel adhesion technologies rely primarily on liquid-based diffusion mechanisms and the formation of covalent bonds, requiring prolonged time to generate adhesion. Here, we present a simple and versatile strategy using dry chitosan polymer films to generate instant adhesion between hydrogel-hydrogel and hydrogel-elastomer surfaces. Using this approach we can achieve extremely high adhesive energies (>3,000 J/m2), which are governed by pH change and non-covalent interactions including H-bonding, Van der Waals forces, and bridging polymer entanglement. Potential examples of biomedical applications are presented, including local tissue cooling, vascular sealing, prevention of surgical adhesions, and prevention of hydrogel dehydration. We expect these findings and the simplicity of this approach to have broad implications for adhesion strategies and hydrogel design.
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Adhesivos , Polímeros , Humanos , Adherencias Tisulares/prevención & control , Adhesivos/química , Elastómeros , Hidrogeles/químicaRESUMEN
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.
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Therapeutic cancer vaccines offer the promise of stimulating the immune system to specifically eradicate tumor cells and establish long-term memory to prevent tumor recurrence. However, despite showing benign safety profiles and the ability to generate Ag-specific cellular responses, cancer vaccines have been hampered by modest clinical efficacy. Lessons learned from these studies have led to the emergence of innovative materials-based strategies that aim to boost the clinical activity of cancer vaccines. In this Brief Review, we provide an overview of the key elements needed for an effective vaccine-induced antitumor response, categorize current approaches to therapeutic cancer vaccination, and explore recent advances in materials-based strategies to potentiate cancer vaccines.
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Vacunas contra el Cáncer , Neoplasias , Humanos , Neoplasias/prevención & control , Neoplasias/tratamiento farmacológico , VacunaciónRESUMEN
Stem cell-derived kidney organoids contain nephron segments that recapitulate morphological and functional aspects of the human kidney. However, directed differentiation protocols for kidney organoids are largely conducted using biochemical signals to control differentiation. Here, the hypothesis that mechanical signals regulate nephrogenesis is investigated in 3D culture by encapsulating kidney organoids within viscoelastic alginate hydrogels with varying rates of stress relaxation. Tubular nephron segments are significantly more convoluted in kidney organoids differentiated in encapsulating hydrogels when compared with those in suspension culture. Hydrogel viscoelasticity regulates the spatial distribution of nephron segments within the differentiating kidney organoids. Consistent with these observations, a particle-based computational model predicts that the extent of deformation of the hydrogel-organoid interface regulates the morphology of nephron segments. Elevated extracellular calcium levels in the culture medium, which can be impacted by the hydrogels, decrease the glomerulus-to-tubule ratio of nephron segments. These findings reveal that hydrogel encapsulation regulates nephron patterning and morphology and suggest that the mechanical microenvironment is an important design variable for kidney regenerative medicine.
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Hidrogeles , Células Madre Pluripotentes , Humanos , Técnicas de Cultivo de Célula/métodos , Riñón , Organoides , Diferenciación CelularRESUMEN
Dermal wounds and their healing are a collection of complex, multistep processes which are poorly recapitulated by existing 2D in vitro platforms. Biomaterial scaffolds that support the 3D growth of cell cultures can better resemble the native dermal environment, while bioelectronics has been used as a tool to modulate cell proliferation, differentiation, and migration. A porous conductive hydrogel scaffold which mimics the properties of dermis, while promoting the viability and growth of fibroblasts is described. As these scaffolds are also electrically conductive, the application of exogenous electrical stimulation directs the migration of cells across and/or through the material. The mechanical properties of the scaffold, as well as the amplitude and/or duration of the electrical pulses, are independently tunable and further influence the resulting fibroblast networks. This biomaterial platform may enable better recapitulation of wound healing and can be utilized to develop and screen therapeutic interventions.
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Fibroblastos , Hidrogeles , Hidrogeles/farmacología , Cicatrización de Heridas , Materiales Biocompatibles/farmacología , Diferenciación Celular , Andamios del TejidoRESUMEN
Bypass graft failure occurs in 20%-50% of coronary and lower extremity bypasses within the first-year due to intimal hyperplasia (IH). TSP-2 is a key regulatory protein that has been implicated in the development of IH following vessel injury. In this study, we developed a biodegradable CLICK-chemistry gelatin-based hydrogel to achieve sustained perivascular delivery of TSP-2 siRNA to rat carotid arteries following endothelial denudation injury. At 21 days, perivascular application of TSP-2 siRNA embedded hydrogels significantly downregulated TSP-2 gene expression, cellular proliferation, as well as other associated mediators of IH including MMP-9 and VEGF-R2, ultimately resulting in a significant decrease in IH. Our data illustrates the ability of perivascular CLICK-gelatin delivery of TSP-2 siRNA to mitigate IH following arterial injury.
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Gelatina , Lesiones del Sistema Vascular , Ratas , Animales , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Hiperplasia , Trombospondinas/genética , Proliferación CelularRESUMEN
Metal surgical pins and screws are employed in millions of orthopedic surgical procedures every year worldwide, but their usability is limited in the case of complex, comminuted fractures or in surgeries on smaller bones. Therefore, replacing such implants with a bone adhesive material has long been considered an attractive option. However, synthesizing a biocompatible bone adhesive with a high bond strength that is simple to apply presents many challenges. To rapidly identify candidate polymers for a biocompatible bone adhesive, we employed a high-throughput screening strategy to assess human mesenchymal stromal cell (hMSC) adhesion toward a library of polymers synthesized via thiol-ene click chemistry. We chose thiol-ene click chemistry because multifunctional monomers can be rapidly cured via ultraviolet (UV) light while minimizing residual monomer, and it provides a scalable manufacturing process for candidate polymers identified from a high-throughput screen. This screening methodology identified a copolymer (1-S2-FT01) composed of the monomers 1,3,5-triallyl-1,3,5-triazine-2,4,6(1H,3H,5H)-trione (TATATO) and pentaerythritol tetrakis (3-mercaptopropionate) (PETMP), which supported highest hMSC adhesion across a library of 90 polymers. The identified copolymer (1-S2-FT01) exhibited favorable compressive and tensile properties compared to existing commercial bone adhesives and adhered to bone with adhesion strengths similar to commercially available bone glues such as Histoacryl. Furthermore, this cytocompatible polymer supported osteogenic differentiation of hMSCs and could adhere 3D porous polymer scaffolds to the bone tissue, making this polymer an ideal candidate as an alternative bone adhesive with broad utility in orthopedic surgery.