The Impact of Epithelial-Mesenchymal Transition and Metformin on Pancreatic Cancer Chemoresistance: A Pathway towards Individualized Therapy.

Globally, pancreatic ductal adenocarcinoma remains among the most aggressive forms of neoplastic diseases, having a dismal prognostic outcome. Recent findings elucidated that epithelial-mesenchymal transition (EMT) can play an important role in pancreatic tumorigenic processes, as it contributes to the manifestation of malignant proliferative masses, which impede adequate drug delivery. An organized literature search with PubMed, Scopus, Microsoft Academic and the Cochrane library was performed for articles published in English from 2011 to 2021 to review and summarize the latest updates and knowledge on the current understanding of EMT and its implications for tumorigenesis and chemoresistance. Furthermore, in the present paper, we investigate the recent findings on metformin as a possible neoadjuvant chemotherapy agent, which affects EMT progression and potentially provides superior oncological outcomes for PDAC patients. Our main conclusions indicate that selectively suppressing EMT in pancreatic cancer cells has a promising therapeutic utility by selectively targeting the chemotherapy-resistant sub-population of cancer stem cells, inhibiting tumor growth via EMT pathways and thereby improving remission in PDAC patients. Moreover, given that TGF-ß1-driven EMT generates the migration of tumor-initiating cells by directly linking the acquisition of abnormal cellular motility with the maintenance of tumor initiating potency, the chemoprevention of TGF-ß1-induced EMT may have promising clinical applications in the therapeutic management of PDAC outcomes.

Evaluation of the activity of a chemo-ablative, thermoresponsive hydrogel in a murine xenograft model of lung cancer.

BACKGROUND: Minimally invasive intratumoural administration of thermoresponsive hydrogels, that transition from liquid to gel in response to temperature, has been proposed as a potential treatment modality for solid tumours. The aim of this study was to assess the inherent cytotoxicity of a poloxamer-based thermoresponsive hydrogel in a murine xenograft model of lung cancer. METHODS: In vitro viability assessment was carried out in a lung cancer (A549) and non-cancerous (Balb/c 3T3 clone A31) cell line. Following intratumoural administration of saline or the thermoresponsive hydrogel to an A549 xenograft model in female Athymic Nude-Foxn1nu mice (n = 6/group), localisation was confirmed using IVIS imaging. Tumour volume was assessed using callipers measurements over 14 days. Blood serum was analysed for liver and kidney damage and ex vivo tissue samples were histologically assessed. RESULTS: The thermoresponsive hydrogel demonstrated a dose-dependent cancer cell-specific toxicity in vitro and was retained in situ for at least 14 days in the xenograft model. Tumour volume increase was statistically significantly lower than saline treated control at day 14 (n = 6, p = 0.0001), with no associated damage of hepatic or renal tissue observed. CONCLUSIONS: Presented is a poloxamer-based thermoresponsive hydrogel, suitable for intratumoural administration and retention, which has demonstrated preliminary evidence of local tumour control, with minimal off-site toxicity.

Evaluation of the Immunomodulatory Effects of All-Trans Retinoic Acid Solid Lipid Nanoparticles and Human Mesenchymal Stem Cells in an A549 Epithelial Cell Line Model.

PURPOSE: To investigate two potential strategies aimed at targeting the inflammatory pathogenesis of COPD: a small molecule, all trans retinoic acid (atRA) and human mesenchymal stem cells (hMSCs). METHODS: atRA was formulated into solid lipid nanoparticles (SLNs) via the emulsification-ultrasonication method, and these SLNs were characterised physicochemically. Assessment of the immunomodulatory effects of atRA-SLNs on A549 cells in vitro was determined using ELISA. hMSCs were suspended in a previously developed methylcellulose, collagen and beta-glycerophosphate hydrogel prior to investigating their immunomodulatory effects in vitro. RESULTS: SLNs provided significant encapsulation of atRA and also sustained its release over 72 h. A549 cells were viable following the addition of atRA SLNs and showed a reduction in IL-6 and IL-8 levels. A549 cells also remained viable following addition of the hMSC/hydrogel formulation - however, this formulation resulted in increased levels of IL-6 and IL-8, indicating a potentially pro-inflammatory effect. CONCLUSION: Both atRA SLNs and hMSCs show potential for modulating the environment in inflammatory disease, though through different mechanisms and leading to different outcomes - despite both being explored as strategies for use in inflammatory disease. atRA shows promise by acting in a directly anti-inflammatory manner, whereas further research into the exact mechanisms and behaviours of hMSCs in inflammatory diseases is required.

Insulin-like growth factor-1 (IGF-1) poly (lactic-co-glycolic acid) (PLGA) microparticles - development, characterisation, and in vitro assessment of bioactivity for cardiac applications.

Aim: The aim of this study was to evaluate the formulation of a synthetic IGF-1 (pIGF-1) in PLGA microparticles (MP). Methods: Poly (lactic-co-glycolic acid) (PLGA) MPs loaded with pIGF-1 were prepared, characterised and evaluated using double emulsion solvent evaporation method. Results: Spherical MPs showed an average particle size of 2 µm, encapsulation efficiency (EE) of 67% and 50% degradation over 15 days. With a view to enhancing retention in the myocardium, the MP formulation was encapsulated in a cross-linked hyaluronic acid hydrogel. pIGF-1 released from MPs and from MPs suspended in hyaluronic acid hydrogel remained bioactive, determined by a significant increase in cellular proliferation of c-kit+ cells. Conclusion: This formulation has potential for loco-regional delivery to damaged myocardium to promote the survival of cardiomyocytes.

Amplification-free detection of microRNAs via a rapid microarray-based sandwich assay.

The detection and profiling of microRNAs are of great interest in disease diagnosis and prognosis. In this paper, we present a method for the rapid amplification-free detection of microRNAs from total RNA samples. In a two-step sandwich assay approach, fluorescently labeled reporter probes were first hybridized with their corresponding target microRNAs. The reaction mix was then added to a microarray to enable their specific capture and detection. Reporter probes were Tm equalized, enabling specificity by adjusting the length of the capture probe while maintaining the stabilizing effect brought about by coaxial base stacking. The optimized assay can specifically detect microRNAs in spiked samples at concentrations as low as 1 pM and from as little as 100 ng of total RNA in 2 h. The detection signal was linear between 1 and 100 pM (R2 = 0.99). Our assay data correlated well with results generated by qPCR when we profiled a select number of breast cancer related microRNAs in a total RNA sample.

Learning to deal with crisis in the home: Part 1--developing community simulation scenarios.

Contemporary health care is increasingly being located in the community. From the evident changes in demographics and general health, it can be derived that the people whom student nurses care for are likely to have multiple comorbidities and be vulnerable to clinical deterioration. These nurses are required to develop a range of transferrable skills to meet the demands of the population. The challenge for educators of preregistration student nurses is to develop educational strategies to prepare them with the skills, knowledge, and confidence necessary to recognise and manage deterioration appropriately in any context. This article is the first of two papers discussing the stimulus, design, and delivery of an educational innovation that focuses on the recognition and management of the deteriorating patient. The article explores current literature about community-focused simulation highlighting the potential learning opportunities resulting from contextualising simulation scenarios specific to the community setting.

Learning to deal with crisis in the home: Part 2 - preparing preregistration students.

The global shift of health care is from acute services to community and primary care. Therefore, registrants must be prepared to work effectively within diverse settings. This article is the second in a series discussing the preparation of nurses for contemporary health-care challenges in the community. In it, we outline the design, implementation, and evaluation of simulated emergency scenarios within an honours degree-level, pre-registration nursing curriculum in Scotland. Over 3 years, 99 final-year students participated in interactive sessions focusing on recognition and management of the deteriorating patient and emergency care. Clinical scenarios were designed and delivered collaboratively with community practitioners. Debriefing challenged the students to reflect on learning and transferability of skills of clinical reasoning and care management to the community context. Students considered the scenarios to be realistic and perceived that their confidence had increased. Development of such simulation exercises is worthy of further debate in education and practice.

Supramolecular hydrogels with reverse thermal gelation properties from (oligo)tyrosine containing block copolymers.

Novel block copolymers comprising poly(ethylene glycol) (PEG) and an oligo(tyrosine) block were synthesized in different compositions by N-carboxyanhydride (NCA) polymerization. It was shown that PEG2000-Tyr(6) undergoes thermoresponsive hydrogelation at a low concentration range of 0.25-3.0 wt % within a temperature range of 25-50 °C. Cryogenic transmission electron microscopy (Cryo-TEM) revealed a continuous network of fibers throughout the hydrogel sample, even at concentrations as low as 0.25 wt %. Circular dichroism (CD) results suggest that better packing of the ß-sheet tyrosine block at increasing temperature induces the reverse thermogelation. A preliminary assessment of the potential of the hydrogel for in vitro application confirmed the hydrogel is not cytotoxic, is biodegradable, and produced a sustained release of a small-molecule drug.

Simple Technique for Microscopic Evaluation of Active Cellular Invasion into 3D Hydrogel Constructs.

Materials that are evaluated for bioengineering purposes are carefully tested to evaluate cellular interactions with respect to biocompatibility and in some cases cell differentiation. A key perspective that is often considered is the ability for decellularized synthetic or natural based matrices to facilitate cell migration or tissue ingrowth. Current methods of measuring cell migration range from simple scratch assays to Boyden chamber inserts and fluorescent imaging of seeded spheroids. Many of these methods require tissue processing for histological analysis and fixing and staining for imaging, which can be difficult and dependent on the stability of the hydrogel subject. Herein we present a simple platform that can be manufactured using 3D printing and easily applied to in vitro cell culture, allowing the researcher to image live cellular migration into a cellular materials. We found this to be an adaptable, cheap, and replicable technique to evaluate cellular interaction that has applications in the research and development of hydrogels for tissue engineering purposes.

Loco-regional drug delivery in oncology: current clinical applications and future translational opportunities.

Introduction: Drug-based treatment regimens for cancer are often associated with off-target toxic side effects and low penetration of the drug at the tumor site leading to patient morbidity and limited efficacy. Loco-regional drug delivery has the potential to increase efficacy while concomitantly reducing toxicity.Areas covered: Clinical applications using loco-regional delivery include intra-arterial drug delivery in retinoblastoma, direct intra-tumoral (IT) injection of ethanol for ablation in hepatocellular carcinoma (HCC) and the use of HIPEC in peritoneal carcinomas. In recent years, there has been a significant increase in both approved products and clinical trials, with a particular emphasis on drug delivery platforms such as drug-eluting beads for HCC and hydrogel platforms for intravesical delivery in bladder cancer.Expert opinion: Development of loco-regional drug-delivery systems has been slow, limited by weak clinical data for early applications and challenges relating to dosing, delivery and retention of drugs at the site of action. However, there is increasing focus on the potential of loco-regional drug delivery when combined with bespoke drug-delivery platforms. With the growth in immunotherapies, the use of IT delivery to drive priming of the anti-tumor response has opened up a new field of opportunity for loco-regional drug delivery.

A Thermoresponsive Chitosan/ß-Glycerophosphate Hydrogel for Minimally Invasive Treatment of Critical Limb Ischaemia.

A reduction in blood supply to any limb causes ischaemia, pain and morbidity. Critical limb ischaemia is the most serious presentation of peripheral vascular disease. One in five patients with critical limb ischaemia will die within six months of diagnosis and one in three will require amputation in this time. Improving blood flow to the limb, via the administration of angiogenic agents, could relieve pain and avoid amputation. Herein, chitosan is combined with ß-glycerophosphate to form a thermoresponsive formulation (chitosan/ß-GP) that will flow through a syringe and needle at room temperature but will form a gel at body temperature. The chitosan/ß-GP hydrogel, with or without the angiogenic molecule desferrioxamine (DFO), was injected into the mouse hind limb, following vessel ligation, to test the ability of the formulations to induce angiogenesis. The effects of the formulations were measured using laser Doppler imaging to determine limb perfusion and CD31 staining to quantify the number of blood vessels. Twenty-eight days following induction of ischaemia, the chitosan/ß-GP and chitosan/ß-GP + 100 µM DFO formulations had significantly (p < 0.001 and p < 0.05, respectively) improved blood flow in the ischaemic limb compared with an untreated control. Chitosan/ß-GP increased vessel number by 1.7-fold in the thigh of the ischaemic limb compared with an untreated control, while chitosan/ß-GP + 100 µM DFO increased vessel number 1.8-fold. Chitosan/ß-GP represents a potential minimally invasive treatment for critical limb ischaemia.

Assessing the Effects of VEGF Releasing Microspheres on the Angiogenic and Foreign Body Response to a 3D Printed Silicone-Based Macroencapsulation Device.

Macroencapsulation systems have been developed to improve islet cell transplantation but can induce a foreign body response (FBR). The development of neovascularization adjacent to the device is vital for the survival of encapsulated islets and is a limitation for long-term device success. Previously we developed additive manufactured multi-scale porosity implants, which demonstrated a 2.5-fold increase in tissue vascularity and integration surrounding the implant when compared to a non-textured implant. In parallel to this, we have developed poly(ε-caprolactone-PEG-ε-caprolactone)-b-poly(L-lactide) multiblock copolymer microspheres containing VEGF, which exhibited continued release of bioactive VEGF for 4-weeks in vitro. In the present study, we describe the next step towards clinical implementation of an islet macroencapsulation device by combining a multi-scale porosity device with VEGF releasing microspheres in a rodent model to assess prevascularization over a 4-week period. An in vivo estimation of vascular volume showed a significant increase in vascularity (* p = 0.0132) surrounding the +VEGF vs. -VEGF devices, however, histological assessment of blood vessels per area revealed no significant difference. Further histological analysis revealed significant increases in blood vessel stability and maturity (** p = 0.0040) and vessel diameter size (*** p = 0.0002) surrounding the +VEGF devices. We also demonstrate that the addition of VEGF microspheres did not cause a heightened FBR. In conclusion, we demonstrate that the combination of VEGF microspheres with our multi-scale porous macroencapsulation device, can encourage the formation of significantly larger, stable, and mature blood vessels without exacerbating the FBR.

Synergistic use of biomaterials and licensed therapeutics to manipulate bone remodelling and promote non-union fracture repair.

Disrupted bone metabolism can lead to delayed fracture healing or non-union, often requiring intervention to correct. Although the current clinical gold standard bone graft implants and commercial bone graft substitutes are effective, they possess inherent drawbacks and are limited in their therapeutic capacity for delayed union and non-union repair. Research into advanced biomaterials and therapeutic biomolecules has shown great potential for driving bone regeneration, although few have achieved commercial success or clinical translation. There are a number of therapeutics, which influence bone remodelling, currently licensed for clinical use. Providing an alternative local delivery context for these therapies, can enhance their efficacy and is an emerging trend in bone regenerative therapeutic strategies. This review aims to provide an overview of how biomaterial design has advanced from currently available commercial bone graft substitutes to accommodate previously licensed therapeutics that target local bone restoration and healing in a synergistic manner, and the challenges faced in progressing this research towards clinical reality.

Supporting the use of sildenafil infusions in paediatric and neonatal intensive care - A compatibility study.

OBJECTIVE: Intravenous (IV) sildenafil, a phosphodiesterase type 5 inhibitor, is increasingly being used for the treatment of pulmonary hypertension (PH) in the paediatric population. Sildenafil (Revatio®) is approved for the treatment of pH in adults where it is administered as a bolus injection. However, in paediatrics it is used off-label and administered by continuous IV infusion. In the critically unwell child, limited IV access necessitates the administration of multiple IV infusions through a single IV lumen. The absence of compatibility data between sildenafil and other IV medications commonly used in this context necessitates the use of a dedicated IV line for sildenafil. The overall aim of this study was to establish the physical and chemical compatibility of sildenafil with commonly administered infusions in the paediatric and neonatal intensive care setting. DESIGN: This study evaluated the chemical and physical compatibility of binary and multiple combinations (n = 42) of sildenafil with adrenaline, noradrenaline, milrinone, vasopressin and heparin. These were tested using three diluents (NaCl 0.9%w/v, Glucose 5%w/v, and Glucose 10%w/v) and two environmental conditions (room temperature and 37 °C) frequently encountered in paediatric or neonatal intensive care units. Prior to drug combination analysis, HPLC methods were developed and optimised to allow for the quantification of drugs in accordance with current pharmaceutical guidance. Binary and multiple drug mixtures of sildenafil were examined for physical and chemical compatibility to establish compatibility. MEASUREMENTS AND MAIN RESULTS: Of the drug combinations not containing heparin, all were deemed compatible with the exception of the five drug mix of Sildenafil 800 µg/mL, Milrinone 200 µg/mL, Vasopressin 0.4Units/mL, Noradrenaline 60 µg/mL, Adrenaline 60 µg/mL at 37 °C, in 10%w/v glucose. All binary or multi drug combinations containing heparin were deemed incompatible. CONCLUSIONS: This research provides support and information to clinicians looking to co-administer sildenafil with other IV medicines thus removing the requirement to subject their patients to multiple intravenous cannula insertion points where IV access is restricted. ARTICLE TWEET: New evidence to support administration of sildenafil infusions in #PedsICU and #nicu- collaboration between @RCSIPharBioMol@FionaSOBrien1 and @OLCHCrumlin @RCSI_Irl @MoninneHowlett #CHI.

Implantable Therapeutic Reservoir Systems for Diverse Clinical Applications in Large Animal Models.

Regenerative medicine approaches, specifically stem cell technologies, have demonstrated significant potential to treat a diverse array of pathologies. However, such approaches have resulted in a modest clinical benefit, which may be attributed to poor cell retention/survival at the disease site. A delivery system that facilitates regional and repeated delivery to target tissues can provide enhanced clinical efficacy of cell therapies when localized delivery of high doses of cells is required. In this study, a new regenerative reservoir platform (Regenervoir) is described for use in large animal models, with relevance to cardiac, abdominal, and soft tissue pathologies. Regenervoir incorporates multiple novel design features essential for clinical translation, with a focus on scalability, mechanism of delivery, fixation to target tissue, and filling/refilling with a therapeutic cargo, and is demonstrated in an array of clinical applications that are easily translated to human studies. Regenervoir consists of a porous reservoir fabricated from a single material, a flexible thermoplastic polymer, capable of delivering cargo via fill lines to target tissues. A radiopaque shear thinning hydrogel can be delivered to the therapy reservoir and multiple fixation methods (laparoscopic tacks and cyanoacrylate bioadhesive) can be used to secure Regenervoir to target tissues through a minimally invasive approach.

Linkage analysis of candidate genes in families with vesicoureteral reflux.

PURPOSE: Vesicoureteral reflux familial clustering implies that genetic factors have a key role in reflux pathogenesis. We identified genes that cause this disease and elucidated the biology and genetics of vesicoureteral reflux. MATERIALS AND METHODS: There were 166 families and 738 individuals, including 319 parents and 419 offspring. The 166 families had 193 affected sib pairs in whom vesicoureteral reflux was confirmed by voiding cystourethrogram. DNA samples were obtained to analyze various candidate genes or regions with a key role in urinary tract development, eg UPK3, UPK2, UPK1B, Chr.10q25.3, KAL1, PAR1 and PAR2. A genome scan was completed in 133 families and the results of genome scan single nucleotide polymorphisms in or closely flanking the candidate genes were investigated. Fine mapping was done to narrow the significant regions and identify potential candidate genes. RESULTS: Lod scores based on the model, proposing a single dominant locus with decreased penetrance, were negative at all loci. Marginally significant nonparametric lod scores were seen at several loci, particularly UPK1B and PAR1. A signal of moderate significance was detected at the region centered on 10q 25.2. CONCLUSIONS: Linkage analysis in a large cohort of vesicoureteral reflux families ruled out UPK3, UPK2, UPK1B, KAL, PAR1 and PAR2 as candidate genes for reflux. Results provide evidence supporting genes and regions that may be worth further study as primary vesicoureteral reflux loci.

Tissue Engineering: Understanding the Role of Biomaterials and Biophysical Forces on Cell Functionality Through Computational and Structural Biotechnology Analytical Methods.

Within the past 25 years, tissue engineering (TE) has grown enormously as a science and as an industry. Although classically concerned with the recapitulation of tissue and organ formation in our body for regenerative medicine, the evolution of TE research is intertwined with progress in other fields through the examination of cell function and behaviour in isolated biomimetic microenvironments. As such, TE applications now extend beyond the field of tissue regeneration research, operating as a platform for modifiable, physiologically-representative in vitro models with the potential to improve the translation of novel therapeutics into the clinic through a more informed understanding of the relevant molecular biology, structural biology, anatomy, and physiology. By virtue of their biomimicry, TE constructs incorporate features of extracellular macrostructure, molecular adhesive moieties, and biomechanical properties, converging with computational and structural biotechnology advances. Accordingly, this mini-review serves to contextualise TE for the computational and structural biotechnology reader and provides an outlook on how the disciplines overlap with respect to relevant advanced analytical applications.

A Custom Radiopaque Thermoresponsive Chemotherapy-Loaded Hydrogel for Intratumoural Injection: An In Vitro and Ex Vivo Assessment of Imaging Characteristics and Material Properties.

PURPOSE: Thermoresponsive hydrogels are gels which have different properties at varying temperatures. The objective of this study was to assess the material characteristics, imaging properties and chemotherapeutic drug release profile of a novel radiopaque thermoresponsive hydrogel in vitro, which is liquid at room temperature but solidifies at body temperature, to determine potential suitability for intratumoural delivery. MATERIALS AND METHODS: An iodinated radiopaque thermoresponsive hydrogel was formulated using iodixanol at a range of concentrations and assessed for sol-gel transition, radiopacity and imaging using CT and US. A lead formulation containing iodixanol at a concentration of 9.22% weight by weight (w/w, g of iodixanol per g of hydrogel) was evaluated in vitro for injectability, disintegration and dual drug release of cisplatin and paclitaxel from the hydrogel formulation. RESULTS: Radiopacity of the hydrogel increased in a concentration-dependent manner, but the highest concentration of iodixanol evaluated in this study (13.83% w/w) adversely affected the sol-gel transition of the hydrogel; therefore, 9.22% w/w iodixanol hydrogel was identified as the lead formulation. This formulation was readily visible on both CT and US. The formulation was hand injectable through a range of clinically relevant devices, had a sustained disintegration profile for up to 28 days and was able to deliver a sustained release of chemotherapeutic drug for up to 10 days. CONCLUSIONS: Favourable in vitro and ex vivo imaging and material characteristics of this thermoresponsive gel are demonstrated, suggesting potential interventional oncology applications for image-guided intratumoural delivery of sustained-release chemotherapy.

A bioresorbable biomaterial carrier and passive stabilization device to improve heart function post-myocardial infarction.

The limited regenerative capacity of the heart after a myocardial infarct results in remodeling processes that can progress to congestive heart failure (CHF). Several strategies including mechanical stabilization of the weakened myocardium and regenerative approaches (specifically stem cell technologies) have evolved which aim to prevent CHF. However, their final performance remains limited motivating the need for an advanced strategy with enhanced efficacy and reduced deleterious effects. An epicardial carrier device enabling a targeted application of a biomaterial-based therapy to the infarcted ventricle wall could potentially overcome the therapy and application related issues. Such a device could play a synergistic role in heart regeneration, including the provision of mechanical support to the remodeling heart wall, as well as providing a suitable environment for in situ stem cell delivery potentially promoting heart regeneration. In this study, we have developed a novel, single-stage concept to support the weakened myocardial region post-MI by applying an elastic, biodegradable patch (SPREADS) via a minimal-invasive, closed chest intervention to the epicardial heart surface. We show a significant increase in %LVEF 14 days post-treatment when GS (clinical gold standard treatment) was compared to GS + SPREADS + Gel with and without cells (p ≤ 0.001). Furthermore, we did not find a significant difference in infarct quality or blood vessel density between any of the groups which suggests that neither infarct quality nor vascularization is the mechanism of action of SPREADS. The SPREADS device could potentially be used to deliver a range of new or previously developed biomaterial hydrogels, a remarkable potential to overcome the translational hurdles associated with hydrogel delivery to the heart.

A collagen cardiac patch incorporating alginate microparticles permits the controlled release of hepatocyte growth factor and insulin-like growth factor-1 to enhance cardiac stem cell migration and proliferation.

Cardiac stem cells (CSCs) represent a logical cell type to exploit as a regenerative treatment option for tissue damage accrued as a result of a myocardial infarction. However, the isolation and expansion of CSCs prior to cell transplantation is time consuming, costly and invasive, and the reliability of cell expansion may also prove to be a major obstacle in the clinical application of CSC-based transplantation therapy after a myocardial infarction. In order to overcome this, we propose the incorporation of growth factor-eluting alginate microparticles into collagen-based scaffolds as an implantable biomaterial to promote the recruitment and expansion of CSCs in the myocardium. In order to obtain scaffolds able to enhance the motogenic and proliferative potential of CSCs, the aim of this work was to achieve a sustained delivery of both hepatocyte growth factor and insulin-like growth factor-1. Both proteins were initially encapsulated in alginate microparticles by spray drying and subsequently incorporated into a collagen scaffold. Microparticles were seen to homogeneously distribute through the interconnected scaffold pore structure. The resulting scaffolds were capable of extending the release of both proteins up to 15 days, a three-fold increase over non-encapsulated proteins embedded in the scaffolds. In vitro assays with isolated CSCs demonstrated that the sustained release of both bioactive proteins resulted in an increased motogenic and proliferative effect. As presently practiced, the isolation and expansion of CSCs for autologous cell transplantation is slow, expensive and difficult to attain. Thus, there is a need for strategies to specifically activate in situ the intrinsic cardiac regenerative potential represented by the CSCs using combinations of growth factors obviating the need for cell transplantation. By favouring the natural regenerative capability of CSCs, it is hypothesized that the cardiac patch presented here will result in positive therapeutic outcomes in MI and heart failure patients in the future. Copyright © 2016 John Wiley & Sons, Ltd.