Hyaluronic acid-British anti-Lewisite as a safer chelation therapy for the treatment of arthroplasty-related metallosis.

Cobalt-containing alloys are useful for orthopedic applications due to their low volumetric wear rates, corrosion resistance, high mechanical strength, hardness, and fatigue resistance. Unfortunately, these prosthetics release significant levels of cobalt ions, which was only discovered after their widespread implantation into patients requiring hip replacements. These cobalt ions can result in local toxic effects-including peri-implant toxicity, aseptic loosening, and pseudotumor-as well as systemic toxic effects-including neurological, cardiovascular, and endocrine disorders. Failing metal-on-metal (MoM) implants usually necessitate painful, risky, and costly revision surgeries. To treat metallosis arising from failing MoM implants, a synovial fluid-mimicking chelator was designed to remove these metal ions. Hyaluronic acid (HA), the major chemical component of synovial fluid, was functionalized with British anti-Lewisite (BAL) to create a chelator (BAL-HA). BAL-HA effectively binds cobalt and rescues in vitro cell vitality (up to 370% of cells exposed to IC50 levels of cobalt) and enhances the rate of clearance of cobalt in vivo (t1/2 from 48 h to 6 h). A metallosis model was also created to investigate our therapy. Results demonstrate that BAL-HA chelator system is biocompatible and capable of capturing significant amounts of cobalt ions from the hip joint within 30 min, with no risk of kidney failure. This chelation therapy has the potential to mitigate cobalt toxicity from failing MoM implants through noninvasive injections into the joint.

Development and evaluation of a concise nurse-driven non-pharmacological delirium reduction workflow for hospitalized patients: An interrupted time series study.

We created a concise nurse-driven delirium reduction workflow with the aim of reducing delirium rates and length of stay for hospitalized adults. Our nurse-driven workflow included five evidence-based daytime "sunrise" interventions (patient room lights on, blinds up, mobilization/out-of-bed, water within patient's reach and patient awake) and five nighttime "turndown" interventions (patient room lights off, blinds down, television off, noise reduction and pre-set bedtime). Interventions were also chosen because fidelity could be quickly monitored twice daily without patient interruption from outside the room. To evaluate the workflow, we used an interrupted time series study design between 06/01/17 and 05/30/22 to determine if the workflow significantly reduced the unit's delirium rate and average length of stay. Our workflow is feasible to implement and monitor and initially significantly reduced delirium rates but not length of stay. However, the reduction in delirium rates were not sustained following the emergence of the COVID-19 pandemic.

Phosphate graphene as an intrinsically osteoinductive scaffold for stem cell-driven bone regeneration.

Synthetic, resorbable scaffolds for bone regeneration have potential to transform the clinical standard of care. Here, we demonstrate that functional graphenic materials (FGMs) could serve as an osteoinductive scaffold: recruiting native cells to the site of injury and promoting differentiation into bone cells. By invoking a Lewis acid-catalyzed Arbuzov reaction, we are able to functionalize graphene oxide (GO) to produce phosphate graphenes (PGs) with unprecedented control of functional group density, mechanical properties, and counterion identity. In aqueous environments, PGs release inducerons, including Ca2+ and PO43- Calcium phosphate graphene (CaPG) intrinsically induces osteogenesis in vitro and in the presence of bone marrow stromal cells (BMSCs), can induce ectopic bone formation in vivo. Additionally, an FGM can be made by noncovalently loading GO with the growth factor recombinant human bone morphogenetic protein 2 (rhBMP-2), producing a scaffold that induces ectopic bone formation with or without BMSCs. The FGMs reported here are intrinsically inductive scaffolds with significant potential to revolutionize the regeneration of bone.

Distribution of single wall carbon nanotubes in the Xenopus laevis embryo after microinjection.

Single wall carbon nanotubes (SWCNTs) are advanced materials with the potential for a myriad of diverse applications, including biological technologies and large-scale usage with the potential for environmental impacts. SWCNTs have been exposed to developing organisms to determine their effects on embryogenesis, and results have been inconsistent arising, in part, from differing material quality, dispersion status, material size, impurity from catalysts and stability. For this study, we utilized highly purified SWCNT samples with short, uniform lengths (145 ± 17 nm) well dispersed in solution. To test high exposure doses, we microinjected > 500 µg ml(-1) SWCNT concentrations into the well-established embryogenesis model, Xenopus laevis, and determined embryo compatibility and subcellular localization during development. SWCNTs localized within cellular progeny of the microinjected cells, but were heterogeneously distributed throughout the target-injected tissue. Co-registering unique Raman spectral intensity of SWCNTs with images of fluorescently labeled subcellular compartments demonstrated that even at regions of highest SWCNT concentration, there were no gross alterations to subcellular microstructures, including filamentous actin, endoplasmic reticulum and vesicles. Furthermore, SWCNTs did not aggregate and localized to the perinuclear subcellular region. Combined, these results suggest that purified and dispersed SWCNTs are not toxic to X. laevis animal cap ectoderm and may be suitable candidate materials for biological applications.

Developing Xenopus embryos recover by compacting and expelling single wall carbon nanotubes.

Single wall carbon nanotubes are high aspect ratio nanomaterials being developed for use in materials, technological and biological applications due to their high mechanical stiffness, optical properties and chemical inertness. Because of their prevalence, it is inevitable that biological systems will be exposed to nanotubes, yet studies of the effects of nanotubes on developing embryos have been inconclusive and are lacking for single wall carbon nanotubes exposed to the widely studied model organism Xenopus laevis (African clawed frog). Microinjection of experimental substances into the Xenopus embryo is a standard technique for toxicology studies and cellular lineage tracing. Here we report the surprising finding that superficial (12.5 ± 7.5 µm below the membrane) microinjection of nanotubes dispersed with Pluronic F127 into one- to two-cell Xenopus embryos resulted in the formation and expulsion of compacted, nanotube-filled, punctate masses, at the blastula to mid-gastrula developmental stages, which we call "boluses." Such expulsion of microinjected materials by Xenopus embryos has not been reported before and is dramatically different from the typical distribution of the materials throughout the progeny of the microinjected cells. Previous studies of microinjections of nanomaterials such as nanodiamonds, quantum dots or spherical nanoparticles report that nanomaterials often induce toxicity and remain localized within the embryos. In contrast, our results demonstrate an active recovery pathway for embryos after exposure to Pluronic F127-coated nanotubes, which we speculate is due to a combined effect of the membrane activity of the dispersing agent, Pluronic F127, and the large aspect ratio of nanotubes.

Pig dorsum model for examining impaired wound healing at the skin-implant interface of percutaneous devices.

Percutaneous medical devices are indispensable in contemporary clinical practice, but the associated incidence of low to moderate mortality infections represents a significant economic and personal cost to patients and healthcare providers. Percutaneous osseointegrated prosthetics also suffer from a similar risk of infection, limiting their clinical acceptance and usage in patients with limb loss. We hypothesized that transepidermal water loss (TEWL) management at the skin-implant interface may improve and maintain a stable skin-to-implant interface. In this study, skin reactions in a 3-month, pig dorsum model were assessed using standard histology, immunohistochemistry, and quantitative image analysis. Immunohistochemical analysis of peri-implant tissue explants showed evidence of: continuous healing (cytokeratin 6+), hypergranulation tissue (procollagen+), hyper-vascularity (collagen 4+), and the presence of fibrocytes (CD45+ and procollagen type 1+). Importantly, the gross skin response was correlated to a previous load-bearing percutaneous osseointegrated prosthetic sheep study conducted in our lab. The skin responses of the two models indicated a potentially shared mechanism of wound healing behavior at the skin-implant interface. Although TEWL management did not reduce skin migration at the skin-implant interface, the correlation of qualitative and quantitative measures validated the pig dorsum model as a high-throughput platform for translational science based percutaneous interface investigations in the future.

A prospective single-center study evaluating the efficacy of the stomach, intestinal, and pylorus-sparing procedure.

BACKGROUND: The stomach, intestinal, and pylorus-sparing (SIPS) procedure is a single-anastomosis duodeno-intestinal bypass used in obesity management. OBJECTIVE: Weight and metabolic outcomes in patients with severe obesity who underwent the SIPS procedure were evaluated in a community hospital-based study. SETTING: Community hospital. METHODS: This single-site prospective study of patients who underwent the SIPS procedure evaluated outcomes at 12 and 24 months. Mean changes in total weight loss and body mass index (BMI) and resolution of gastroesophageal reflux disease (GERD), obstructive sleep apnea (OSA), hypertension, type 2 diabetes (T2D), and hyperlipidemia were evaluated. RESULTS: At baseline, 185 patients were enrolled; mean weight and BMI were 144.0 kg and 52.2 kg/m2, respectively. Data for 88 (47.6%) and 29 (15.7%) patients who completed follow-up at 12 and 24 months, respectively, were available. At 12 months, mean total weight loss was 35.6% (weight reduction of 51.3 kg) and BMI reduction of 17.8 points were achieved and were maintained for the 29 patients who completed 24-month follow-up. No leaks or infections occurred. Complications occurred in 8 patients (.4%) and were not serious. Resolution of GERD, OSA, hypertension, T2D, and hyperlipidemia achieved in 87.1%, 59.2%, 32.7%, 93.1%, and 87.6% of patients, respectively, at 12 months was maintained at 24 months. Nutritional deficiency was absent. CONCLUSIONS: Patients who underwent the SIPS procedure had meaningful reductions in weight and BMI, and many had resolution of metabolic co-morbidities; procedural complication rates were low. Our results support that the SIPS procedure is a safe and effective primary treatment for clinically severe obesity in a community-based hospital setting.

GC/MS method for positive detection of Bacillus anthracis endospores.

A simple method was developed for detection of Bacillus anthracis (BA) endospores and for differentiation of them from other species in the Bacillus cereus group. Chemical profiles that include lipids (i.e., fatty acids), carbohydrates (i.e., sugars), and the spore-specific biomarker, dipicolinic acid, were generated by one-step thermochemolysis (TCM) at 140 °C in 5 min to provide specific biomarker signatures. Anthrose, which is a biomarker characteristic of the B. cereus group of bacteria, was determined from a fragment produced by TCM. Surprisingly, several virulent BA strains contained very low levels of anthrose, which confounded their detection. A statistical discrimination algorithm was constructed using a combination of biomarkers, which was robust against different growth conditions (medium and temperature). Fifteen endospore-forming Bacillus species were confirmed in a statistically designed test (~90%) using the algorithm, including six BA strains (four virulent isolates), five B. thuringiensis (BT) isolates, and one isolate each for B. cereus (BC), B. mycoides (BM), B. atrophaeus (BG), and B. subtilis (BS). The detection limit for B. anthracis was found to be 50,000 endospores, on the basis of the GC/MS detection limits for 3-methyl-2-butenoic acid methyl ester, which is the biomarker derived from TCM of anthrose.

Ultra-low binder content 3D printed calcium phosphate graphene scaffolds as resorbable, osteoinductive matrices that support bone formation in vivo.

Bone regenerative engineering could replace autografts; however, no synthetic material fulfills all design criteria. Nanocarbons incorporated into three-dimensional printed (3DP) matrices can improve properties, but incorporation is constrained to low wt%. Further, unmodified nanocarbons have limited osteogenic potential. Functionalization to calcium phosphate graphene (CaPG) imparts osteoinductivity and osteoconductivity, but loading into matrices remained limited. This work presents ultra-high content (90%), 3DP-CaPG matrices. 3DP-CaPG matrices are highly porous (95%), moderately stiff (3 MPa), and mechanically robust. In vitro, they are cytocompatible and induce osteogenic differentiation of human mesenchymal stem cells (hMSCs), indicated by alkaline phosphatase, mineralization, and COL1α1 expression. In vivo, bone regeneration was studied using a transgenic fluorescent-reporter mouse non-union calvarial defect model. 3DP-CaPG stimulates cellular ingrowth, retains donor cells, and induces osteogenic differentiation. Histology shows TRAP staining around struts, suggesting potential osteoclast activity. Apparent resorption of 3DP-CaPG was observed and presented no toxicity. 3DP-CaPG represents an advancement towards a synthetic bone regeneration matrix.

Quantification of uptake and localization of bovine serum albumin-stabilized single-wall carbon nanotubes in different human cell types.

Single-wall carbon nanotubes (SWCNTs) possess many unique, inherent properties that make them attractive materials for application in medical and biological technologies. Development of concentrated SWCNT dispersions of isolated nanotubes that retain SWCNTs' inherent properties with minimal negative cellular effects is essential to fully realize the potential of SWCNTs in biotechnology. It is shown that bovine serum albumin (BSA), a common and well-characterized model blood serum protein, can individually disperse SWCNTs at concentrations of up to 0.3 mg mL(-1) while retaining SWCNTs' optical properties. Uptake into human mesenchymal stem cells (hMSC) and HeLa cells is quantified, revealing strikingly high concentrations of 86 ± 33 × 10(6) and 21 ± 13 × 10(6) SWCNTs per cell, respectively, without any apparent acute deleterious cellular effects. Through high-resolution confocal Raman spectroscopy and imaging, it is established that SWCNT-BSAs are preferentially localized intracellularly, especially in the cytoplasm of both hMSCs and HeLa cells. The uptake and localization results demonstrate the efficacy of BSA as a biocompatible dispersant and a mediator of bioactivity. BSA is widely available and inexpensive, which make these concentrated, highly-dispersed, noncovalently modified SWCNT-BSAs suitable for the development of SWCNT-based biotechnologies.

Single wall carbon nanotubes enter cells by endocytosis and not membrane penetration.

BACKGROUND: Carbon nanotubes are increasingly being tested for use in cellular applications. Determining the mode of entry is essential to control and regulate specific interactions with cells, to understand toxicological effects of nanotubes, and to develop nanotube-based cellular technologies. We investigated cellular uptake of Pluronic copolymer-stabilized, purified ~145 nm long single wall carbon nanotubes (SWCNTs) through a series of complementary cellular, cell-mimetic, and in vitro model membrane experiments. RESULTS: SWCNTs localized within fluorescently labeled endosomes, and confocal Raman spectroscopy showed a dramatic reduction in SWCNT uptake into cells at 4°C compared with 37°C. These data suggest energy-dependent endocytosis, as shown previously. We also examined the possibility for non-specific physical penetration of SWCNTs through the plasma membrane. Electrochemical impedance spectroscopy and Langmuir monolayer film balance measurements showed that Pluronic-stabilized SWCNTs associated with membranes but did not possess sufficient insertion energy to penetrate through the membrane. SWCNTs associated with vesicles made from plasma membranes but did not rupture the vesicles. CONCLUSIONS: These measurements, combined, demonstrate that Pluronic-stabilized SWCNTs only enter cells via energy-dependent endocytosis, and association of SWCNTs to membrane likely increases uptake.

The Blanket Effect: How Turning the World Upside Down Reveals the Nature of Graphene Oxide Cytocompatibility.

Extensive cytocompatibility testing of 2D nanocarbon materials including graphene oxide (GO) has been performed, but results remain contradictory. Literature has yet to account for settling-although sedimentation is visible to the eye and physics suggests that even individual graphenic flakes will settle. To investigate settling, a series of functional graphenic materials (FGMs) with differing oxidation levels, functionalities, and physical dimensions are synthesized. Though zeta potential indicates colloidal stability, significant gravitational settling of the FGMs is theoretically and experimentally demonstrated. By creating a setup to culture cells in traditional and inverted orientations in the same well, a "blanket effect" is demonstrated in which FGMs settle out of solution and cover cells at the bottom of the well, ultimately reducing viability. Inverted cells protected from the blanket effect are unaffected. Therefore, these results demonstrate that settling is a crucial factor that must be considered for FGM cytocompatibility experiments.

Bioactive, Ion-Releasing PMMA Bone Cement Filled with Functional Graphenic Materials.

Graphene oxide and functionalized graphenic materials (FGMs) have promise as platforms for imparting programmable bioactivity to poly(methyl methacrylate) (PMMA)-based bone cement. To date, however, graphenic fillers have only been feasible in PMMA cements at extremely low loadings, limiting the bioactive effects. At higher loadings, graphenic fillers decrease cement strength by aggregating and interfering with curing process. Here, these challenges are addressed by combining bioactive FGM fillers with a custom cement formulation. These cements contain an order of magnitude more graphenic filler than previous reports. Even at 1 wt% FGM, these cements have compressive strengths of 78- 88 MPa, flexural strengths of 74-81 MPa, and flexural stiffnesses of 1.8-1.9 GPa, surpassing the ASTM requirements for bone cement and competing with traditional PMMA cement. Further, by utilizing designer FGMs with programmed bioactivity, these cements demonstrate controlled release of osteogenic calcium ions (releasing a total of 5 ± 2 µmol of Ca2+ per gram of cement over 28 d) and stimulate a 290% increase in expression of alkaline phosphatase in human mesenchymal stem cells in vitro. Also, design criteria are described to guide creation of future generations of bone cements that utilize FGMs as platforms to achieve dynamic biological activity.

Outcomes Following Implementation of a Hospital-Wide, Multicomponent Delirium Care Pathway.

BACKGROUND: Delirium is associated with poor clinical outcomes that could be improved with targeted interventions. OBJECTIVE: To determine whether a multicomponent delirium care pathway implemented across seven specialty nonintensive care units is associated with reduced hospital length of stay (LOS). Secondary objectives were reductions in total direct cost, odds of 30-day hospital readmission, and rates of safety attendant and restraint use. METHODS: This retrospective cohort study included 22,708 hospitalized patients (11,018 preintervention) aged ≥50 years encompassing seven nonintensive care units: neurosciences, medicine, cardiology, general and specialty surgery, hematology-oncology, and transplant. The multicomponent delirium care pathway included a nurse-administered delirium risk assessment at admission, nurse-administered delirium screening scale every shift, and a multicomponent delirium intervention. The primary study outcome was LOS for all units combined and the medicine unit separately. Secondary outcomes included total direct cost, odds of 30-day hospital readmission, and rates of safety attendant and restraint use. RESULTS: Adjusted mean LOS for all units combined decreased by 2% post intervention (proportional change, 0.98; 95% CI, 0.96-0.99; P = .0087). Medicine unit adjusted LOS decreased by 9% (proportional change, 0.91; 95% CI, 0.83-0.99; P = .028). For all units combined, adjusted odds of 30-day readmission decreased by 14% (odds ratio [OR], 0.86; 95% CI, 0.80-0.93; P = .0002). Medicine unit adjusted cost decreased by 7% (proportional change, 0.93; 95% CI, 0.89-0.96; P = .0002). CONCLUSION: This multicomponent hospital-wide delirium care pathway intervention is associated with reduced hospital LOS, especially for patients on the medicine unit. Odds of 30-day readmission decreased throughout the entire cohort.

Polyester functional graphenic materials as a mechanically enhanced scaffold for tissue regeneration.

Traditional metal implants such as titanium, cobalt, and chromium have found wide utility in medicine; however, these come with a risk of toxicity. To overcome metal-related toxicity and enable degradability, polyesters including polycaprolactone (PCL), polylactic acid (PLA), and polyglycolic acid (PGA) show promise for the replacement of various biomedical applications of metals due to their accepted biocompatibility and FDA approval. However, polyesters are less stiff than their metallic counterparts, limiting their application to non-load bearing injury sites, such as fixation hardware for fingers. To improve mechanical properties, graphene oxide (GO)-polyester composites are a promising class of biodegradable scaffolds. Initial reports of these composites are encouraging, but mechanical properties still fall short. Traditional composites rely on non-covalent association between GO and the polyesters, which often leads to failure at the interface and weakens the overall strength of the material. Herein, we present a strategy for attachment of these FDA-approved polyesters onto a derivative of GO using a robust covalent bond. By covalently functionalizing the graphenic backbone with polyesters and without metal catalysts, we create functional graphenic materials (FGMs) to not only simultaneously retain biodegradability and compatibility, but also mechanically strengthen PCL, PLA, and PGA; we observed an average increase in the Young's modulus of over 140% compared to the graphenic backbone. These polyester-functionalized FGMs are a promising platform technology for tissue implants.

Covalent conjugation of bioactive peptides to graphene oxide for biomedical applications.

Graphene is a valuable material in biomedical implant applications due to its mechanical integrity, long-range order, and conductivity; but graphene must be chemically modified to increase biocompatibility and maximize functionality in the body. Here, we developed a foundational synthetic method for covalently functionalizing a reduced GO with bioactive molecules, focusing on synthetic peptides that have shown osteogenic or neurogenic capability as a prototypical example. X-ray photoelectron spectroscopy provides evidence that the peptide is covalently linked to the graphenic backbone. These peptide-graphene (Pep-G) conjugate materials can be processed into mechanically robust, three-dimensional constructs. Differences in their electrostatic charges allow the Pep-G conjugates to form self-assembled, layer-by-layer coatings. Further, the Pep-G conjugates are cytocompatible and electrically conductive, leading us to investigate their potential as regenerative scaffolds, as conductive surfaces can stimulate bone and nerve regeneration. Notably, PC12 cells grown on an electrically stimulated Pep-G scaffold demonstrated enhanced adhesion and neurite outgrowth compared to the control. The functionalization strategy developed here can be used to conjugate a wide variety of bioactive molecules to graphene oxide to create cell-instructive surfaces for biomedical scaffold materials.

Functional Graphenic Materials That Seal Condenser Tube Leaks in Situ.

Undesirable condenser tube leaks frequently occur in power plants, resulting in reduced power output, increased burden on downstream systems, and substantial revenue losses. Current techniques such as wood flour provide temporary in situ remediation but lack adhesive properties to form stable seals. Here, we report the development of in situ sealants for long-term defect repair. The carboxylic acids on graphene oxides and Claisen graphene were used as chemical handles to covalently install a bio-inspired, adhesive catechol, generating a class of functional graphenic material (FGM) sealants. FGM sealants outperformed unfunctionalized scaffolds with enhanced antimicrobial activity to prevent fouling (up to 55% reduction) and superior cohesive properties to promote stable seals. Further, FGM sealants were adhesive, effectively sealing defects in a model experiment, whereas unfunctionalized scaffolds did not display any sealant capacity.

Injectable amine functionalized graphene and chondroitin sulfate hydrogel with potential for cartilage regeneration.

Damaged cartilage does not readily heal and often requires surgical intervention that only modestly improves outcomes. A synthetic material that could be injected and covalently crosslinked in situ to form a bioactive, mechanically robust scaffold that promotes stem cell chondrogenic differentiation holds promise for next-generation treatment of cartilage lesions. Here, Johnson-Claisen rearrangement chemistry was performed on graphene oxide (GO) to enable functionalization with a primary amine covalently bound to the graphenic backbone through a chemically stable linker. The primary amines are used to form covalent crosslinks with chondroitin sulfate, an important component of cartilage that promotes regeneration, to form a hydrogel (EDAG-CS). The EDAG-CS system gels in situ within 10 min, and the graphenic component imparts improved mechanical properties, including stiffness (320% increase) and toughness (70% increase). EDAG-CS hydrogels are highly porous, resistant to degradation, and enable the growth of human mesenchymal stem cells and their deposition of collagen matrix. This system has potential to improve clinical outcomes of patients with cartilage damage.

Viscoelastic response of human skin to low magnitude physiologically relevant shear.

Percutaneous implants are a family of devices that penetrate the skin and all suffer from the same problems of infection because the skin seal around the device is not optimal. Contributing to this problem is the mechanical discontinuity of the skin/device interface leading to stress concentrations and micro-trauma that chronically breaks any seal that forms. In this paper, we have quantified the mechanical behavior of human skin under low-magnitude shear loads over physiological relevant frequencies. Using a stress-controlled rheometer, we have performed isothermal (37 degrees C) frequency response experiments between 0.628 and 75.39 rad/s at 0.5% and 0.04% strain on whole skin and dermis-only, respectively. Step-stress experiments of 5 and 10 Pa shear loads were also conducted as were strain sweep tests (6.28 rad/s). Measurements were made of whole human skin and skin from which the epidermis was removed (dermis-only). At low frequencies (0.628-10 rad/s), the moduli are only slightly frequency dependent, with approximate power-law scaling of the moduli, G' approximately G'' approximately omega(beta), yielding beta=0.05 for whole skin and beta=0.16 for dermis-only samples. Step-stress experiments revealed three distinct phases. The intermediate phase included elastic "ringing" (damped oscillation) which provided new insights and could be fit to a mathematical model. Both the frequency and step-stress response data suggest that the epidermis provides an elastic rigidity and dermis provides viscoelasticity to the whole skin samples. Hence, whole skin exhibited strain hardening while the dermis-only demonstrated stress softening under step-stress conditions. The data obtained from the low-magnitude shear loads and frequencies that approximate the chronic mechanical environment of a percutaneous implant should aid in the design of a device with an improved skin seal.

Covalently-controlled drug delivery via therapeutic methacrylic tissue adhesives.

Medical cyanoacrylate adhesives have the potential to eliminate the need for sutures but face challenges to widespread implementation due to their brittleness and release of formaldehyde upon degradation. To overcome these limitations, we used molecular design to create therapeutic methacrylic (TMA) monomers to impart tunable mechanical properties, decreased formaldehyde release, and covalently-controlled bioactivity to commercial cyanoacrylate adhesives. The small molecule therapeutics ibuprofen, acetaminophen, and benzocaine were covalently tethered to the carbonyl of methacrylate using anhydride, ester, and amide bonds. When these TMAs were incorporated into n-butyl cyanoacrylate (BCA) tissue adhesives, the resulting TMA-BCA materials provided release of the therapeutics across a range of time scales according to the reactivity of the tether bond to hydrolysis. The anhydride-tether TMA-BCA adhesive delivered ibuprofen on the same order of magnitude and time scale as topical medications (12 ± 6 mg per g adhesive after 3.4 h). TMA-BCA adhesives also produced less formaldehyde than standard BCA adhesive, showed promising cytocompatibility, and adhered effectively to porcine skin. Further, the anhydride, ester, and amide tether TMA-BCA adhesives exhibited a range of shear moduli, with those containing rigid aromatic amide groups being stiffer, and those with flexible alkyl segments being less stiff, which could enable these adhesives to be tailored to match the mechanical properties of target tissues. The amide-tether TMA-BCA adhesive also showed a 219% increase in toughness compared to BCA. Overall, TMAs represent a platform technology that can be used to build adaptable and bioactive tissue adhesives.