Enhancing cognitive control with transcranial magnetic stimulation in subject-specific frontoparietal networks.

BACKGROUND: Cognitive control processes, including those involving frontoparietal networks, are highly variable between individuals, posing challenges to basic and clinical sciences. While distinct frontoparietal networks have been associated with specific cognitive control functions such as switching, inhibition, and working memory updating functions, there have been few basic tests of the role of these networks at the individual level. METHODS: To examine the role of cognitive control at the individual level, we conducted a within-subject excitatory transcranial magnetic stimulation (TMS) study in 19 healthy individuals that targeted intrinsic ("resting") frontoparietal networks. Person-specific intrinsic networks were identified with resting state functional magnetic resonance imaging scans to determine TMS targets. The participants performed three cognitive control tasks: an adapted Navon figure-ground task (requiring set switching), n-back (working memory), and Stroop color-word (inhibition). OBJECTIVE: Hypothesis: We predicted that stimulating a network associated with externally oriented control [the "FPCN-B" (fronto-parietal control network)] would improve performance on the set switching and working memory task relative to a network associated with attention (the Dorsal Attention Network, DAN) and cranial vertex in a full within-subjects crossover design. RESULTS: We found that set switching performance was enhanced by FPCN-B stimulation along with some evidence of enhancement in the higher-demand n-back conditions. CONCLUSION: Higher task demands or proactive control might be a distinguishing role of the FPCN-B, and personalized intrinsic network targeting is feasible in TMS designs.

Polyphenols as a partial replacement for vitamin E in nursery pig diets.

A total of 300 pigs (241 × 600; DNA, Columbus, NE; initially 6.0 ±â€…0.01 kg) were used in a 42-d trial to determine the effects of vitamin E levels and partially replacing vitamin E with a polyphenol (Cabanin CSD, R2 Argo, Denmark) on growth performance, complete blood count, serum thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), and cytokine panel. Sixty pens of pigs were weighed and allotted to one of the five dietary treatments in a completely randomized design with 12 pens per treatment. A control treatment was formulated to provide 15 IU/kg of vitamin E equivalence from vitamin E. This control treatment was then used as a base for three replacement strategy diets to determine the effects of replacing an additional 60 IU/kg of vitamin E with polyphenol in diets containing a basal level of vitamin E requirement estimate (15 IU/kg). First, an additional 60 IU/kg of vitamin E was added for a total of 75 IU/kg of vitamin E equivalence. Second, 50% of the additional vitamin E (30 IU/kg) was replaced with the equivalency of polyphenol. Third, all 60 IU/kg of the additional vitamin E was replaced with the equivalency of polyphenol. To evaluate whether there are negative effects of feeding nursery pigs a high level of polyphenol, a fifth treatment was formulated to provide 575 IU/kg of vitamin E equivalence with 75 IU/kg from vitamin E and 500 IU/kg from polyphenol. Whole blood and serum samples were collected on days 10 and 42, and pig weights and feed disappearance were measured on days 10, 21, 31, 38, and 42. For growth performance, increasing vitamin E equivalence tended to improve (quadratic, P < 0.10) gain-to-feed ratio (G:F) from days 10 to 21, and tended to improve (linear, P < 0.10) G:F from days 21 to 42 and 0 to 42. There was a vitamin E equivalence × day interaction (P = 0.050) for serum SOD activity. Increasing vitamin E equivalence increased (linear, P < 0.05) serum SOD activity on day 42 but not on days 10 (P > 0.10). For serum cytokines, there was no evidence of differences (P > 0.10) between treatments and vitamin E equivalence. Moreover, there was no evidence of differences (P > 0.10) in all response variables between the three replacement strategies throughout the entire periods. In summary, increasing vitamin E equivalence tended to improve G:F, which may be related to the improved SOD activity. Furthermore, polyphenol can effectively replace vitamin E provided above the vitamin E requirement to provide similar benefits from increasing vitamin E equivalence.

Periplasmic methionine sulfoxide reductase (MsrP)-a secondary factor in stress survival and virulence of Salmonella Typhimurium.

Among others, methionine residues are highly susceptible to host-generated oxidants. Repair of oxidized methionine (Met-SO) residues to methionine (Met) by methionine sulfoxide reductases (Msrs) play a chief role in stress survival of bacterial pathogens, including Salmonella Typhimurium. Periplasmic proteins, involved in many important cellular functions, are highly susceptible to host-generated oxidants. According to location in cell, two types of Msrs, cytoplasmic and periplasmic are present in S. Typhimurium. Owing to its localization, periplasmic Msr (MsrP) might play a crucial role in defending the host-generated oxidants. Here, we have assessed the role of MsrP in combating oxidative stress and colonization of S. Typhimurium. ΔmsrP (mutant strain) grew normally in in-vitro media. In comparison to S. Typhimurium (wild type), mutant strain showed mild hypersensitivity to HOCl and chloramine-T (ChT). Following exposure to HOCl, mutant strain showed almost similar protein carbonyl levels (a marker of protein oxidation) as compared to S. Typhimurium strain. Additionally, ΔmsrP strain showed higher susceptibility to neutrophils than the parent strain. Further, the mutant strain showed very mild defects in survival in mice spleen and liver as compared to wild-type strain. In a nutshell, our results indicate that MsrP plays only a secondary role in combating oxidative stress and colonization of S. Typhimurium.

Prediction of Diabetes Mellitus Progression Using Supervised Machine Learning.

Diabetic peripheral neuropathy (DN) is a serious complication of diabetes mellitus (DM) that can lead to foot ulceration and eventual amputation if not treated properly. Therefore, detecting DN early is important. This study presents an approach for diagnosing various stages of the progression of DM in lower extremities using machine learning to classify individuals with prediabetes (PD; n = 19), diabetes without (D; n = 62), and diabetes with peripheral neuropathy (DN; n = 29) based on dynamic pressure distribution collected using pressure-measuring insoles. Dynamic plantar pressure measurements were recorded bilaterally (60 Hz) for several steps during the support phase of walking while participants walked at self-selected speeds over a straight path. Pressure data were grouped and divided into three plantar regions: rearfoot, midfoot, and forefoot. For each region, peak plantar pressure, peak pressure gradient, and pressure-time integral were calculated. A variety of supervised machine learning algorithms were used to assess the performance of models trained using different combinations of pressure and non-pressure features to predict diagnoses. The effects of choosing various subsets of these features on the model's accuracy were also considered. The best performing models produced accuracies between 94-100%, showing the proposed approach can be used to augment current diagnostic methods.

Matrix Degradability Contributes to the Development of Salivary Gland Progenitor Cells with Secretory Functions.

Synthetic matrices that are cytocompatible, cell adhesive, and cell responsive are needed for the engineering of implantable, secretory salivary gland constructs to treat radiation induced xerostomia or dry mouth. Here, taking advantage of the bioorthogonality of the Michael-type addition reaction, hydrogels with comparable stiffness but varying degrees of degradability (100% degradable, 100DEG; 50% degradable, 50DEG; and nondegradable, 0DEG) by cell-secreted matrix metalloproteases (MMPs) were synthesized using thiolated HA (HA-SH), maleimide (MI)-conjugated integrin-binding peptide (RGD-MI), and MI-functionalized peptide cross-linkers that are protease degradable (GIW-bisMI) or nondegradable (GIQ-bisMI). Organized multicellular structures developed readily in all hydrogels from dispersed primary human salivary gland stem cells (hS/PCs). As the matrix became progressively degradable, cells proliferated more readily, and the multicellular structures became larger, less spherical, and more lobular. Immunocytochemical analysis showed positive staining for stem/progenitor cell markers CD44 and keratin 5 (K5) in all three types of cultures and positive staining for the acinar marker α-amylase under 50DEG and 100DEG conditions. Quantitatively at the mRNA level, the expression levels of key stem/progenitor markers KIT, KRT5, and ETV4/5 were significantly increased in the degradable gels as compared to the nondegradable counterparts. Western blot analyses revealed that imparting matrix degradation led to >3.8-fold increase in KIT expression by day 15. The MMP-degradable hydrogels also promoted the development of a secretary phenotype, as evidenced by the upregulation of acinar markers α-amylase (AMY), aquaporin-5 (AQP5), and sodium-potassium chloride cotransporter 1 (SLC12A2). Collectively, we show that cell-mediated matrix remodeling is necessary for the development of regenerative pro-acinar progenitor cells from hS/PCs.

Primary Tubercular Osteomyelitis Affecting the Mandibular Condyle - A Case Report.

Rationale: Primary orofacial tuberculosis (TB) accounts for <3% of all cases of TB. TB of the mandibular condyle is often misdiagnosed owing to its rarity. Patient Concerns: This report presents a 19-year-old female who presented with a painful swelling over the right preauricular region. The radiographic evaluation suggested a diagnosis of suppurative osteomyelitis of the condyle. Diagnosis: Clinically, the aetiology of the swelling was considered as infective. The histopathological examination of the resected specimen showed tuberculous granuloma and the polymerase chain reaction came positive.This confirms the diagnosis of tubercular osteomyelitis. Mantoux test and sputum acid-fast bacilli were found to be negative. Treatment: The patient was subjected to sequestrectomy with high condylectomy and systemic multidrug antitubercular regimen for 6 months. Outcomes: There was a resolution of infection postoperatively with subsequent regeneration of healthy bone. Take-away Lessons: Early identification and prompt diagnosis is imperative for better treatment outcomes.

Simulated Attack Reveals How Lesions Affect Network Properties in Poststroke Aphasia.

Aphasia is a prevalent cognitive syndrome caused by stroke. The rarity of premorbid imaging and heterogeneity of lesion obscures the links between the local effects of the lesion, global anatomic network organization, and aphasia symptoms. We applied a simulated attack approach in humans to examine the effects of 39 stroke lesions (16 females) on anatomic network topology by simulating their effects in a control sample of 36 healthy (15 females) brain networks. We focused on measures of global network organization thought to support overall brain function and resilience in the whole brain and within the left hemisphere. After removing lesion volume from the network topology measures and behavioral scores [the Western Aphasia Battery Aphasia Quotient (WAB-AQ), four behavioral factor scores obtained from a neuropsychological battery, and a factor sum], we compared the behavioral variance accounted for by simulated poststroke connectomes to that observed in the randomly permuted data. Global measures of anatomic network topology in the whole brain and left hemisphere accounted for 10% variance or more of the WAB-AQ and the lexical factor score beyond lesion volume and null permutations. Streamline networks provided more reliable point estimates than FA networks. Edge weights and network efficiency were weighted most highly in predicting the WAB-AQ for FA networks. Overall, our results suggest that global network measures provide modest statistical value beyond lesion volume when predicting overall aphasia severity, but less value in predicting specific behaviors. Variability in estimates could be induced by premorbid ability, deafferentation and diaschisis, and neuroplasticity following stroke.SIGNIFICANCE STATEMENT Poststroke, the remaining neuroanatomy maintains cognition and supports recovery. However, studies often use small, cross-sectional samples that cannot fully model the interactions between lesions and other variables that affect networks in stroke. Alternate methods are required to account for these effects. "Simulated attack" models are computational approaches that apply virtual damage to the brain and measure their putative consequences. Using a simulated attack model, we estimated how simulated damage to anatomic networks could account for language performance. Overall, our results reveal that global network measures can provide modest statistical value predicting overall aphasia severity, but less value in predicting specific behaviors. These findings suggest that more theoretically precise network models could be necessary to robustly predict individual outcomes in aphasia.

Language Tasks and the Network Control Role of the Left Inferior Frontal Gyrus.

Recent work has combined cognitive neuroscience and control theory to make predictions about cognitive control functions. Here, we test a link between whole-brain theories of semantics and the role of the left inferior frontal gyrus (LIFG) in controlled language performance using network control theory (NCT), a branch of systems engineering. Specifically, we examined whether two properties of node controllability, boundary and modal controllability, were linked to semantic selection and retrieval on sentence completion and verb generation tasks. We tested whether the controllability of the left IFG moderated language selection and retrieval costs and the effects of continuous θ burst stimulation (cTBS), an inhibitory form of transcranial magnetic stimulation (TMS) on behavior in 41 human subjects (25 active, 16 sham). We predicted that boundary controllability, a measure of the theoretical ability of a node to integrate and segregate brain networks, would be linked to word selection in the contextually-rich sentence completion task. In contrast, we expected that modal controllability, a measure of the theoretical ability of a node to drive the brain into specifically hard-to-reach states, would be linked to retrieval on the low-context verb generation task. Boundary controllability was linked to selection and to the ability of TMS to reduce response latencies on the sentence completion task. In contrast, modal controllability was not linked to performance on the tasks or TMS effects. Overall, our results suggest a link between the network integrating role of the LIFG and selection and the overall semantic demands of sentence completion.

Purification and preliminary characterization of four Rel homologues from pathogenic bacteria: Implications for species-specific inhibitor design.

Resistance to antibiotics is a serious concern to treat infectious diseases and also, for food preservation. Existing antibiotics generally inhibit enzymes participating in key bacterial processes, such as formation of cell wall, replication, transcription and translation. However, bacteria have rapidly evolved new mechanisms to combat these antibiotics and it hence becomes indispensable to identify newer targets and identify/design inhibitors against them. Another concern is that most antibiotics are broad spectrum; they largely bind and inhibit the active site of the target enzyme. Rel proteins, which synthesize (and hydrolyze) (p)ppGpp in response to a variety of stress encountered by bacteria, is a profitable target owing to its distinct absence in humans and an intricate regulation of the catalytic activities. Inactivation of (p)ppGpp synthesis by Rel, disables bacterial survival in Mycobacterium tuberculosis and Staphylococcus aureus, while inactivating the hydrolysis activity was lethal. The poor MIC values of the currently known Rel inhibitors present a distinct opportunity to develop better inhibitors and warrants a detailed structural characterization and understanding of the complex regulation in Rel proteins. It will open new avenues for the design of effective, species-specific inhibitors. In an attempt to identify unique sites for inhibitor design using structure-based approaches, we initiate a study of Rel homologues from four different pathogenic bacteria, in order to compare their attributes with well characterized Rel homologues. Here, we present cloning, over-expression, purification and preliminary characterization of these four homologues; and suggest similarities and differences that can be exploited for inhibitor design.

Dermoscopic Characterization of Dermatophytosis: A Preliminary Observation.

INTRODUCTION: Dermatophytosis has become resistant and relapsing infection in India. Diagnosis of dermatophytosis is easy, however, poses diagnostic challenge in partial treatment, steroid abuse. Dermoscopy is noninvasive tool for diagnosis of many infestations and infections. Dermoscopy in dermatophytosis is not well documented. We evaluated dermatoscopic patterns to correlate with histopathological changes. MATERIALS AND METHODS: Study was conducted in tertiary hospital after obtaining ethical clearance and informed consent. DermLite 3 dermoscope was used to examine the lesions. Polarized and nonpolarized modes were used and ultrasound gel was utilized. Potassium hydroxide mount and skin biopsy was done to confirm the diagnosis. RESULTS: About 30 patients with 16 males and 14 females were present. Median duration was 3.5 months and median age was 30 years. The most common site was waist and crural area affecting 20 (66.66%). Dermoscopy revealed brown to black dots, globules, and white scales in all patients (100.0%). Lesions of shorter duration (26.66%) demonstrated red dots, dotted vessels, reddish-brown dots, and globules, and brown to black dots and globules were noted in lesions of longer duration (73.33%). Hair changes were noted in five (16.66%) patients. CONCLUSION: Dermoscopy showed particular patterns in dermatophytosis. Patterns were consistent irrespective of age, sex, and site of involvement. Presence of reddish-brown and black globules with white scales was found to be the most characteristic dermoscopic feature.

A Clinical and Radiographic Evaluation of the Efficacy of Nanohydroxyapatite (Sybograf™) versus Bioactive Calcium Phosphosilicate Putty (Novabone®) in the Treatment of Human Periodontal Infrabony Defects: A Randomized Clinical Trial.

AIM: The aim of this study is to compare and to evaluate clinically and radiographically the bone regeneration and the amount of bone fill (BL) between nanocrystalline hydroxyapatite (Nc-HA) (Sybograf™) and bioactive synthetic NovaBone Putty in the treatment of intrabony component of periodontal osseous defects. MATERIALS AND METHODS: Twenty sites in 20 patients, within the age range of 25-55 years, showing intrabony defects were selected and divided into Group I (Nc-HA) and Group II (Bioactive synthetic NovaBone Putty). All the selected sites were assessed with the clinical and radiographic parameters such as plaque index, gingival index, sulcus bleeding index, probing pocket depth, clinical attachment level, gingival recession, and radiographic BL. All the clinical and radiographic parameter values obtained at different intervals (baseline, 3, and 6 and 9 months) were subjected to statistical analysis. RESULTS: A statistically significant reduction in pocket depth of 4.400 ± 0.843 mm (Group I), 3.800 ± 0.789 mm (Group II) and gain in clinical attachment level of 6.2 mm (Group I), 5.9 mm (Group II) were recorded at the end of the study. A slight increase in gingival recession was observed. The mean percentage changes in the amount of radiographic BL of Group II and Group I were significant, However, when compared between the groups, there is no significant difference in BL observed. CONCLUSION: Both the graft materials appear to have nearly comparable effects, with nanocrystalline hydroxyapatite (Sybograf™), displaying slightly superior effect over bioactive glass especially in relation to clinical parameters. However, long-term, controlled clinical trials are required to confirm these findings.

Neuroimmune Semaphorin 4A in Cancer Angiogenesis and Inflammation: A Promoter or a Suppressor?

Neuroimmune semaphorin 4A (Sema4A), a member of semaphorin family of transmembrane and secreted proteins, is an important regulator of neuronal and immune functions. In the nervous system, Sema4A primarily regulates the functional activity of neurons serving as an axon guidance molecule. In the immune system, Sema4A regulates immune cell activation and function, instructing a fine tuning of the immune response. Recent studies have shown a dysregulation of Sema4A expression in several types of cancer such as hepatocellular carcinoma, colorectal, and breast cancers. Cancers have been associated with abnormal angiogenesis. The function of Sema4A in angiogenesis and cancer is not defined. Recent studies have demonstrated Sema4A expression and function in endothelial cells. However, the results of these studies are controversial as they report either pro- or anti-angiogenic Sema4A effects depending on the experimental settings. In this mini-review, we discuss these findings as well as our data on Sema4A regulation of inflammation and angiogenesis, which both are important pathologic processes underlining tumorigenesis and tumor metastasis. Understanding the role of Sema4A in those processes may guide the development of improved therapeutic treatments for cancer.

Gene editing for corneal disease management.

Gene editing has recently emerged as a promising technology to engineer genetic modifications precisely in the genome to achieve long-term relief from corneal disorders. Recent advances in the molecular biology leading to the development of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) and CRISPR-associated systems, zinc finger nucleases and transcription activator like effector nucleases have ushered in a new era for high throughput in vitro and in vivo genome engineering. Genome editing can be successfully used to decipher complex molecular mechanisms underlying disease pathophysiology, develop innovative next generation gene therapy, stem cell-based regenerative therapy, and personalized medicine for corneal and other ocular diseases. In this review we describe latest developments in the field of genome editing, current challenges, and future prospects for the development of personalized gene-based medicine for corneal diseases. The gene editing approach is expected to revolutionize current diagnostic and treatment practices for curing blindness.

Biofunctional hydrogels for skeletal muscle constructs.

Hydrogel scaffolds encapsulating C2C12 mouse skeletal muscle cells have been engineered as in vitro constructs towards regenerative medicine therapies for the enhancement and inducement of functional skeletal muscle formation. Previous work has largely involved two-dimensional (2D) muscle strips, naturally occurring hydrogels and incomplete examination of the effects of the scaffold and/or biological functionalization on myogenic differentiation in a controllable manner. The goal of this study was to identify key properties in functionalized poly(ethylene glycol) (PEG)-maleimide (MAL) synthetic hydrogels that promote cell attachment, proliferation and differentiation for the formation of multinucleated myotubes and functional skeletal muscle tissue constructs. Significant differences in myoblast viability were observed as a function of cell seeding density, polymer weight percentage and bioadhesive ligands. The identified optimized conditions for cell survival, required for myotube development, were carried over for differentiation assays. PEG hydrogels (5% weight/volume), functionalized with 2.0 mm RGD adhesive peptide and crosslinked with protease-cleavable peptides, incubated for 3 days before supplementation with 2% horse serum, significantly increased expression of differentiated skeletal muscle markers by 50%; 17% more multinucleated cells and a 40% increase in the number of nuclei/differentiated cell compared to other conditions. Functionality of cell-laden hydrogels was demonstrated by a 20% decrease in the extruded length of the hydrogel when stimulated with a contractile agent, compared to 7% for a saline control. This study provided strategies to engineer a three-dimensional (3D) microenvironment, using synthetic hydrogels to promote the development of differentiated muscle tissue from skeletal muscle progenitor cells to form contractile units. Copyright © 2014 John Wiley & Sons, Ltd.

Prevalence and severity of periodontal disease in type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus) patients in Bangalore city: An epidemiological study.

BACKGROUND: Our objective was to study the prevalence and severity of periodontal disease in type 2 diabetes mellitus (DM) patients in Bangalore city. MATERIALS AND METHODS: Four hundred and eight type 2 DM patients (Study Group) and 100 non-diabetic patients (Control Group) among the age group of 35-75 years were included in the study. The study group was divided based on Glycated hemoglobin levels into well, moderately and poorly controlled. Relevant information regarding age, oral hygiene habits and personal habits was obtained from the patients. Diabetic status and mode of anti-diabetic therapy of the study group was obtained from the hospital records with consent from the patient. Community periodontal index (CPI) was used to assess the periodontal status. The results were statistically evaluated. RESULTS: The mean CPI score and the number of missing teeth was higher in diabetics compared with non-diabetics, and was statistically significant (P=0.000), indicating that prevalence and extent of periodontal disease was more frequent and more severe in diabetic patients. The risk factors like Glycated hemoglobin, duration of diabetes, fasting blood sugar, personal habits and oral hygiene habits showed a positive correlation with periodontal destruction, whereas mode of anti-diabetic therapy showed a negative correlation according to the multiple regression analysis. The odds ratio of a diabetic showing periodontal destruction in comparison with a non-diabetic was 1.97, 2.10 and 2.42 in well, moderately and poorly controlled diabetics, respectively. CONCLUSION: Our study has made an attempt to determine the association between type 2 DM (NIDDM) and periodontal disease in Bangalore city. It was found that type 2 DM (non-insulin-dependent diabetes mellitus [NIDDM]) subjects manifested relatively higher prevalence and severity of periodontal disease as compared with non-diabetics.

Adrenomedullin, periodontitis, diabetes-unraveling the equivocal relationship: A clinicobiochemical cross-sectional study.

CONTEXT: Antimicrobial proteins and peptides constitute a diverse class of host-defense molecules that act early to combat invasion and infection with bacteria and other microorganisms. Among the various antimicrobial peptides in the oral cavity, adrenomedullin (ADM), a cationic peptide, is found in gingival crevicular fluids (GCFs) in amounts twice as high in periodontal disease sites as healthy sites. Studies have also shown that plasma levels of ADM increased in patients with type 2 diabetes mellitus as compared with controls. AIMS: This clinico-biochemical study was undertaken to try to decipher the probable link between ADM, diabetes and periodontitis. MATERIALS AND METHODS: The study comprised of 90 patients who were divided into three groups based on community periodontal index scores and diabetes status. Probing pocket depth and clinical attachment level were measured in all subjects. GCF was collected from all the participants using micropipettes and blood samples were collected from subjects in Groups III, for analysis of glycated hemoglobin. ADM levels were measured in GCF samples by the enzyme-linked immunosorbent assay. STATISTICAL ANALYSIS USED: The data obtained were subjected to analysis of variance, Bonferroni test and Pearson's correlation. RESULTS: An increase in GCF levels of ADM from periodontal health to disease and in periodontitis patients with type 2 diabetes was noted. CONCLUSIONS: Increase in GCF levels of ADM from periodontal health to disease and in periodontitis patients with type 2 diabetes reinforces the perio-systemic interlink concept.

Dual delivery of hepatocyte and vascular endothelial growth factors via a protease-degradable hydrogel improves cardiac function in rats.

Acute myocardial infarction (MI) caused by ischemia and reperfusion (IR) is the most common cause of cardiac dysfunction due to local cell death and a temporally regulated inflammatory response. Current therapeutics are limited by delivery vehicles that do not address spatial and temporal aspects of healing. The aim of this study was to engineer biotherapeutic delivery materials to harness endogenous cell repair to enhance myocardial repair and function. We have previously engineered poly(ethylene glycol) (PEG)-based hydrogels to present cell adhesive motifs and deliver VEGF to promote vascularization in vivo. In the current study, bioactive hydrogels with a protease-degradable crosslinker were loaded with hepatocyte and vascular endothelial growth factors (HGF and VEGF, respectively) and delivered to the infarcted myocardium of rats. Release of both growth factors was accelerated in the presence of collagenase due to hydrogel degradation. When delivered to the border zones following ischemia-reperfusion injury, there was no acute effect on cardiac function as measured by echocardiography. Over time there was a significant increase in angiogenesis, stem cell recruitment, and a decrease in fibrosis in the dual growth factor delivery group that was significant compared with single growth factor therapy. This led to an improvement in chronic function as measured by both invasive hemodynamics and echocardiography. These data demonstrate that dual growth factor release of HGF and VEGF from a bioactive hydrogel has the capacity to significantly improve cardiac remodeling and function following IR injury.