Injectable Gel Research Articles

Gold Nanoparticle-Functionalized Reverse Thermal Gel for Tissue Engineering Applications.

Utilizing polymers in cardiac tissue engineering holds promise for restoring function to the heart following myocardial infarction, which is associated with grave morbidity and mortality. To properly mimic native cardiac tissue, materials must not only support cardiac cell growth but also have inherent conductive properties. Here, we present an injectable reverse thermal gel (RTG)-based cardiac cell scaffold system that is both biocompatible and conductive. Following the synthesis of a highly functionalizable, biomimetic RTG backbone, gold nanoparticles (AuNPs) were chemically conjugated to the backbone to enhance the system's conductivity. The resulting RTG-AuNP hydrogel supported targeted survival of neonatal rat ventricular myocytes (NRVMs) for up to 21 days when cocultured with cardiac fibroblasts, leading to an increase in connexin 43 (Cx43) relative to control cultures (NRVMs cultured on traditional gelatin-coated dishes and RTG hydrogel without AuNPs). This biomimetic and conductive RTG-AuNP hydrogel holds promise for future cardiac tissue engineering applications.

A fundamental approach to design of injectable high-content gel polymer electrolyte for activated carbon electrode supercapacitors

An injectable high-content gel polymer electrolyte (GPE) was designed so that highly-entangled polymer matrix was situated in bulk electrolyte of supercapacitors (SCs) and SBP+/BF4− ions were more concentrated in pores of activated carbon (AC) particles, thereby facilitating ion transport. Compared with the SCs containing the liquid electrolyte (1 M SBPBF4/AN), the SCs containing the injectable GPE showed 5% higher capacitance (12% reduced Warburg resistance) at 20 ℃ and 52% higher capacitance (95% retention) after 16-h storage at 80 ℃ (boiling point of AN). This study provides insight into the developments of novel GPE processes for high-energy AC electrode SCs.

Redox-active injectable gel using polyion complex to achieve sustained release of exenatide and enhance therapeutic efficacy for the treatment of type 2 diabetes.

To provide sustained release of exenatide and enhance therapeutic efficacy for the treatment of type 2 diabetes compared to the existing products for exenatide, we developed an exenatide-loaded, redox-active, injectable gel (Exe@RIG). This injectable gel is formed by a polyion complex (PIC) comprising three components, (1) cationic polyamine-poly(ethylene glycol)-polyamine triblock copolymer possessing reactive oxygen species (ROS)-scavenging moieties as side chains, (2) anionic poly(acrylic acid), and (3) exenatide. The mixture formed exenatide-loaded PIC flower micelles at room temperature, which immediately converted to a gel under physiological conditions. Owing to electrostatic interactions between exenatide and the PIC gel network, RIG was able to provide sustained release of exenatide without a significant initial burst. Subcutaneous injection of Exe@RIG once a week prevented the increase in glucose concentration significantly in db/db mice compared to those in control groups. In addition, Exe@RIG suppressed the degeneration of pancreatic islets, which is reported to be caused by increased ROS. Our result indicates that Exe@RIG has the potential to provide a long acting exenatide as well as enhanced efficacy in the treatment of type 2 diabetes compared to the existing products. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1107-1113, 2019.

3395 An Injectable Sulfonated Reversible Thermal Gel for Controlled and Localized Delivery of Vascular Endothelial Growth Factor to Promote Cardiac Protection After a Myocardial Infarction

OBJECTIVES/SPECIFIC AIMS: This study aims to evaluate an injectable sulfonated reserve thermal gel (SPSHU-PNIPAM) for angiogenic growth factor delivery by examining the vascularization and cardioprotective properties of the polymer system. This study could lead to clinical translation by moving into larger animal studies and eventually clinical trials. The success of this study was determined by analyzing the results of echocardiography data on cardiac function (ejection fraction, fractional shortening, and left ventricle inner diameter) and assessment of histological staining on cardiac tissue (fibrotic tissue formation, infarct size, wall thinning, blood vessel cell counts, and vessel size quantification) after MI. Five groups were compared for this study: saline, VEGF, SPSHU-PNIPAM, SPSHU-PNIPAM loaded with VEGF, and no injection (sham). Significant statistical differences between control groups and polymer injection groups, when p < 0.05, indicates successful outcomes from this study. METHODS/STUDY POPULATION: SPSHU-PNIPAM Polymer Synthesis: SPSHU-PNIPAM was synthesized as previously described. Briefly, PSHU was synthesized with N-BOC serinol, urea, and HDI at 90 °C for 7 days. PSHU was deprotected in DCM and TFA at room temperature for 45 min. PNIPAM was conjugated to the deprotected PSHU using EDC and NHS at room temperature for 24 h. PSHU-PNIPAM was sulfonated with 1,3-propanesultone and potassium tert-butoxide at 60 °C for 3 days. Surgical Procedure: Male C57BL/6 mice weighing 24-28 g were anaesthetized using isoflurane and artificial ventilation provided. A small left thoracotomy incision was made at the left fourth intercostal space to expose the heart, and the proximal left anterior descending coronary artery was ligated for 45 min. The coronary artery was then released and 30 μl injections of saline, SPSHU-PNIPAM (1% w/v), bolus VEGF (200 ng), or SPSHU-PNIPAM + VEGF (1%, 200 ng) were injected intramyocardially at the infarcted site and the incision closed. Echocardiography and Histological Staining: Standard serial transthoracic echocardiography was performed while simultaneously recording ECG to assess cardiac morphology and left ventricular function. Immunohistochemistry and histology staining procedures were used to identify: fibrotic tissue formation, infarct size, wall thinning, blood vessel cell counts, and vessel size quantification. These were performed according to manufacturer instructions or by previously published criteria. Statistical Analysis: Two-tailed t-test assuming unequal variances was used to determine significant differences between two groups. Analysis of variance (ANOVA) was used to determine significant differences between three or more groups followed by Tukey-Kramer to determine significant differences between two groups as appropriate. Statistical significance was considered when p < 0.05.

An injectable sulfonated reversible thermal gel for therapeutic angiogenesis to protect cardiac function after a myocardial infarction

BackgroundCardiovascular disease and myocardial infarction are associated with high mortality and morbidity and a more effective treatment remains a major clinical need. The intramyocardial injection of biomaterials has been investigated as a potential treatment for heart failure by providing mechanical support to the myocardium and reducing stress on cardiomyocytes. Another treatment approach that has been explored is therapeutic angiogenesis that requires careful spatiotemporal control of angiogenic drug delivery. An injectable sulfonated reversible thermal gel composed of a polyurea conjugated with poly(N-isopropylacrylamide) and sulfonate groups has been developed for intramyocardial injection with angiogenic factors for the protection of cardiac function after a myocardial infarction.ResultsThe thermal gel allowed for the sustained, localized release of VEGF in vivo with intramyocardial injection after two weeks. A myocardial infarction reperfusion injury model was used to evaluate therapeutic benefits to cardiac function and vascularization. Echocardiography presented improved cardiac function, infarct size and ventricular wall thinning were reduced, and immunohistochemistry showed improved vascularization with thermal gel injections. The thermal gel alone showed cardioprotective and vascularization properties, and slightly improved further with the additional delivery of VEGF. An inflammatory response evaluation demonstrated the infiltration of macrophages due to the myocardial infarction was more significant compared to the foreign body inflammatory response to the thermal gel. Detecting DNA fragments of apoptotic cells also demonstrated potential anti-apoptotic effects of the thermal gel.ConclusionThe intramyocardial injection of the sulfonated reversible thermal gel has cardioprotective and vascularization properties for the treatment of myocardial infarction.

Covalently polysaccharide-based alginate/chitosan hydrogel embedded alginate microspheres for BSA encapsulation and soft tissue engineering

Hydrogels based scaffolds are very promising materials for a wide range of medical applications including tissue engineering and drug delivery. This study reports a covalently cross-linked composite hydrogel embedded with microspheres basing natural polysaccharides as a protein delivery system for soft tissue engineering. This biodegradable composite hydrogel derived from water-soluble chitosan and alginate derivatives upon mixing, without addition of chemical cross-linking agents. The gelation is attributed to the Schiff-base reaction between amino and aldehyde groups of N-succinyl chitosan (N-Chi) and oxidized alginate (OAlg), respectively. Meanwhile, gel-like microspheres were prepared with a diameter of 2–10 μm by conjugating sodium alginate with Ca2+ in an aqueous emulsion via the emulsion cross-linking technique. Bull Serum Albumin (BSA) was encapsulated into alginate gel microspheres and subsequently incorporated into OAlg/N-Chi hydrogels to produce a composite scaffold. In the current work, gelation rate, morphology, mechanical properties, swelling ratio, in vitro degradation and BSA release of the composite scaffolds were examined. The results show that mechanical and stable properties of gel scaffolds can be significantly improved by embedding alginate microspheres. The alginate microspheres can serve as a filler to toughen the soft OAlg/N-Chi hydrogels. Compressive modulus of composite gel scaffolds containing 0.5 mL volume of microspheres was 57.3 KPa, which was higher than the control hydrogel without microspheres. Moreover, the controlled release of BSA encapsulated within this composite hydrogels showed significantly lower rate when compared with control hydrogel or microspheres alone. These characteristics provide a potential opportunity to use this injectable composite gel scaffold in protein delivery and soft tissue engineering applications.

Randomized Double-Blind Controlled Study on the Safety and Efficacy of a Novel Injectable Cross-linked Hyaluronic Gel for the Correction of Moderate-to-Severe Nasolabial Wrinkles

The current study compares two hyaluronic acid fillers, Ial System Duo and Belotero Basic/Balance, for the treatment of wrinkles. This is a single-center, double-blind randomized controlled study. Inclusion criteria consisted of subjects with bilateral nasolabial wrinkles. Each subject was treated with both products: One was applied on the right side and the other on the left side of the face. The quantity of product injected and any problems or local reactions (erythema, edema, pain or itching) were recorded and reassessed at 3 and 6months and then monthly until complete absorption of the product. The Wrinkle Severity Rating Scale (WSRS) and the Global Aesthetic Improvement Scale (GAIS) were used for the assessment, as well as an ultrasound measurement of the skin thickness. Complete data were available for 59 subjects. At 3 and 6months, both products showed improvement in the WSRS and GAIS score in the areas treated compared to pre-treatment assessments, although no significant differences were observed between them. No resulting significant differences were observed on skin thickness among the two products, which were completely reabsorbed in 285 ± 34days (Ial System Duo) and 277 ± 34days (Belotero Basic/Balance; Student's t test: p = 0.2181). No significant differences were observed with regard to the subject's satisfaction and adverse events. The Ial System Duo achieves long-term permanence (more than 9months confirmed by ultrasound) in correction of moderate and severe wrinkles, similar to Belotero Basic/Balance. Both products showed a high safety profile and a high degree of subject and physician satisfaction. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Injectable and biodegradable phospholipid-based phase separation gel for sustained delivery of insulin.

Long-term and daily injection of insulin for the treatment of diabetes mellitus often bring great suffering to patients. In order to reduce injection frequency and improve patient compliance, an injectable in-situ forming phospholipid-based phase separation gel (PPSG) was formulated in the present study. Insulin was loaded into PPSG for sustained and controlled delivery, which could maintain the bioactivity of insulin during its release process. The in-situ formation and degradation behavior of PPSG in vivo indicated that solvent exchange could be the driving force for phase transition and that phospholipid vesicle formation and burst could be the mechanism of drug release and gel degradation. In the foreign body response study, PPSG implants were demonstrated to be biodegradable, and the degree of inflammation and fibrotic responses could be decreased by increasing the phospholipid content. The applicability of insulin on PPSG was justified by studying the drug release property and the bioactivity of insulin in PPSG. As a result, the insulin-loaded PPSG showed a sustained drug release behavior and a long-lasting hypoglycemic effect in diabetic rats. In conclusion, PPSG is of good biocompatibility and biodegradability, which is promising to serve as a sustained insulin delivery system and improve patient compliance effectively.

Injectable Nanoclay Gels for Angiogenesis

The retention and sustained activity of therapeutic proteins at delivery sites are goals of regenerative medicine. Vascular endothelial growth factor (VEGF) has significant potential in promoting the growth and regeneration of blood vessels but is intrinsically labile. This is exacerbated by the inflammatory microenvironments at sites requiring regeneration. For VEGF to be efficacious it may require a carrier that stabilises it, protects it from degradation and retains it at a site of interest. In this study we tested the hypothesis that injectable nanoclay gels composed of Laponite XLGTM can stabilise VEGF and retain it in active form for therapeutic delivery. To achieve this, VEGF was incorporated in Laponite gels and its activity tested at a range of concentrations using in vitro cell culture tubulogenesis assays and in vivo angiogenesis assays. We found that VEGF-Laponite gels enhanced tubulogenesis in a dose-dependent manner in vitro. When administered subcutaneously in vivo Laponite was retained at an injection site for up to a period of three weeks and promoted a 4-fold increase in blood vessel formation compared with alginate or vehicle controls as confirmed by CD31 staining. Notably, in contrast to alginate, Laponite gels did not release VEGF, indicating a strong interaction between the growth factor and the nanoclay, and suggesting that Laponite enhancement of VEGF efficacy is due to its retention at an implantation site over a prolonged period. Our approach provides a robust method for delivery of bioactive recombinant VEGF without the necessity for complex hydrogel or protein engineering.

Development and characterization of an immunomodulatory and injectable system composed of collagen modified with trifunctional oligourethanes and silica.

Immunomodulatory biomaterials have emerged as a promising approach to engineer wound healing. To achieve this task, the bioactivity of the biomaterials and an easy application are two key desirable characteristics. This work reports an injectable gel system containing immune cells primed for wound healing. By combining the self-assembly of type I collagen, cross-linked with trifunctional oligourethanes, and silica particle entrapment, the structured collagen network acts as a delivery vehicle for macrophages. This structured collagen network primes the macrophages for an anti-inflammatory response. Rheological measurements suggest that the mixture of liquid precursors can be safely stored at low temperatures and low pH (4 °C, pH 3) for at least one month. After pH neutralization and injection, gels with a storage modulus of 50-80 Pa are obtained in five minutes. Several immunocytochemistry and ELISA tests strongly suggest that mouse and human macrophages are stimulated by the material to up-regulate the production of anti-inflammatory cytokines, while down-regulating the production of pro-inflammatory cytokines. The injection of gel in an ex vivo inflammation model of intervertebral discs demonstrated that it is possible to transit from a pro-inflammatory to an anti-inflammatory microenvironment. Altogether, the results suggest that this gel can polarize the macrophage response and promote a surrounding anti-inflammatory microenvironment ready for injection for wound healing applications.

First clinical experience with a new injectable recombinant human collagen scaffold combined with autologous platelet-rich plasma for the treatment of lateral epicondylar tendinopathy (tennis elbow)

Lateral epicondylitis is a tendinopathy of the common extensor origin at the elbow. When traditional conservative treatment fails, more effective therapies are needed. Vergenix Soft Tissue Repair (STR) Matrix (CollPlant Ltd., Ness-Ziona, Israel) is an injectable gel composed of cross-linked bioengineered recombinant human type I collagen combined with autologous platelet-rich plasma (STR/PRP). The complex forms a collagen-fibrin matrix that promotes cell migration and tissue repair. Based on positive outcomes from preclinical trials, this study is the first clinical trial of STR/PRP on tendinopathy. We hypothesized that STR/PRP would be a safe and effective treatment for lateral epicondylar tendinopathy. Patients with chronic lateral epicondylitis underwent treatment with STR/PRP. Outcome assessment included grip strength, functional disability, and changes in sonographic tendon appearance for up to 6 months after treatment. The study enrolled 40 patients. No systemic or local severe adverse events were reported. Clinical evaluation revealed an improvement in the mean Patient-Rated Tennis Elbow Evaluation score from 64.8 before treatment and showed a 59% reduction at 6 months. The 12-Item Short-Form Health Survey questionnaire showed improvement from a mean score of 30.7 to 37.7 at the final follow-up. Grip strength increased from 28.8 kg at baseline to 36.8 kg at 6 months. Improvements in sonographic tendon appearance were evident among 68% of patients. STR/PRP is a safe treatment that effectively induces clinically significant improvements in elbow symptoms and general well-being as well as objective measures of strength and imaging of the common extensor tendon within 6 months of treatment of elbow tendinopathy recalcitrant to standard treatments.

Autologous platelet-rich gel for facial rejuvenation and wrinkle amelioration: A pilot study.

The demand for safe and minimally invasive soft tissue augmentation procedures has increased. Recently, a novel injectable gel based on the autologous platelet rich in growth factor (PRGF) technology has been developed to provide long-term shape and volume stability. It can be customized into low (LVG) or high viscosity (HVG) gel forms to meet different dermatological requirements. The mechanical and biological properties of both gel forms have been evaluated. The clinical efficacy and safety of this autologous procedure were also evaluated. Growth factor content and biomechanical properties of both gel forms were determined. The in vitro biological capacity on human dermal fibroblasts proliferation was assessed. Clinical performance analysis over ten patients was evaluated by standardized macrophotographs, 3D topographic images, and ultrasound analysis over periocular and nasolabial areas. Both gel types showed similar growth factor concentration. HVG showed a higher stiffness profile indicating its suitability for deeper tissue defect viscosupplementation while LVG showed optimal rheologic characteristics for superficial volumization. Both gels showed a noticeable biostability after catalytic enzyme degradation. Both forms significantly increased the mitogenic activity of dermal fibroblasts. All patients referred to be highly satisfied and presented optimal clinical results after one month. Overall clinical improvement was maintained for 16weeks. At the end of the study, the ultrasound examination revealed a cutaneous regenerative effect. No adverse events occurred. This preliminary study suggests that autologous platelet gels have desirable mechanical and bioactive properties and allows moderate wrinkle reduction and efficient facial volume reposition with natural results.

Injectable Biodegradable Chitosan-Alginate 3D Porous Gel Scaffold for mRNA Vaccine Delivery.

mRNA vaccines have proven to be more stable, effective, and specific than protein/peptide-based vaccines in stimulating both humoral and cellular immune response. However, mRNA's fast degradation rate and low-transfection efficiency in vivo impede its potential in vaccination. Recent research in gene delivery has focused on nonviral vaccine carriers and either implantable or injectable delivery systems to improve transgene expression in vivo. Here, an injectable chitosan-alginate gel scaffold for the local delivery of mRNA vaccines is reported. Gel scaffold biodegradation rates and biocompatibility are quantified. Scaffold-mediated mRNA in vivo transgene expression as well as ovalbumin antigen specific cellular and humoral immune responses are evaluated in vivo. Luciferase reporter protein expression resulting from mRNA lipoplex-loaded gel scaffolds is five times higher than systemic injection. Compared to systemic injections of naked mRNA or mRNA:lipoplexes, elevated levels of T cell proliferation and IFN-γ secretion are seen with in vivo scaffold-mediated mRNA lipoplex delivery. Furthermore, a humoral response (ovalbumin antigen specific IgG levels) is observed as early as week 1 for scaffold-mediated mRNA lipoplex delivery, while protein-based immunization did not elicit IgG production until 2 weeks post-injection. Results suggest that injectable scaffold mRNA vaccine delivery maybe a viable alternative to traditional nucleic acid immunization methods.

Recombinant Human Bone Morphogenetic Protein 6 Delivered Within Autologous Blood Coagulum Restores Critical Size Segmental Defects of Ulna in Rabbits.

BMP2 and BMP7, which use bovine Achilles tendon-derived absorbable collagen sponge and bovine bone collagen as scaffold, respectively, have been approved as bone graft substitutes for orthopedic and dental indications. Here, we describe an osteoinductive autologous bone graft substitute (ABGS) that contains recombinant human BMP6 (rhBMP6) dispersed within autologous blood coagulum (ABC) scaffold. The ABGS is created as an injectable or implantable coagulum gel with rhBMP6 binding tightly to plasma proteins within fibrin meshwork, as examined by dot-blot assays, and is released slowly as an intact protein over 6 to 8 days, as assessed by ELISA. The biological activity of ABGS was examined in vivo in rats (Rattus norvegicus) and rabbits (Oryctolagus cuniculus). In a rat subcutaneous implant assay, ABGS induced endochondral bone formation, as observed by histology and micro-CT analyses. In the rabbit ulna segmental defect model, a reproducible and robust bone formation with complete bridging and restoration of the defect was observed, which is dose dependent, as determined by radiographs, micro-CT, and histological analyses. In ABGS, ABC scaffold provides a permissive environment for bone induction and contributes to the use of lower doses of rhBMP6 compared with BMP7 in bovine bone collagen as scaffold. The newly formed bone undergoes remodeling and establishes cortices uniformly that is restricted to implant site by bridging with host bone. In summary, ABC carrier containing rhBMP6 may serve as an osteoinductive autologous bone graft substitute for several orthopedic applications that include delayed and nonunion fractures, anterior and posterior lumbar interbody fusion, trauma, and nonunions associated with neurofibromatosis type I.

An Injectable Reverse Thermal Gel for Minimally Invasive Coverage of Mouse Myelomeningocele

BackgroundMyelomeningocele (MMC) results in lifelong neurologic and functional deficits. Currently, prenatal repair of MMC closes the defect, resulting in a 50% reduction in postnatal ventriculoperitoneal shunting. However, this invasive fetal surgery is associated with significant morbidities to mother and baby. We have pioneered a novel reverse thermal gel (RTG) to cover MMC defects in a minimally invasive manner. Here, we test in-vitro RTG long-term stability in amniotic fluid and in vivo application in the Grainy head-like 3 (Grhl3) mouse MMC model. Materials and methodsRTG stability in amniotic fluid (in-vitro) was monitored for 6 mo and measured using gel permeation chromatography and solution–gel transition temperature (lower critical solution temperature). E16.5 Grhl3 mouse fetuses were injected with the RTG or saline and harvested on E19.5. Tissue was assessed for RTG coverage of the gross defect and inflammatory response by immunohistochemistry for macrophages. ResultsPolymer backbone molecular weight and lower critical solution temperature remain stable in amniotic fluid after 6 mo. Needle injection over the MMC of Grhl3 fetuses successfully forms a stable gel that covers the entire defect. On harvest, some animals demonstrate >50% RTG coverage. RTG injection is not associated with inflammation. ConclusionsOur results demonstrate that the RTG is a promising candidate for a minimally invasive approach to patch MMC. We are now poised to test our RTG patch in the large preclinical ovine model used to evaluate prenatal repair of MMC.

Trimethoxysilyl end-capped hyperbranched polyglycidol/polycaprolactone copolymers for cell delivery and tissue repair: synthesis, characterisation and aqueous solution properties

New PCL-HBPG/SiHBPG triblock copolymers composed of a polycaprolactone (PCL) core with two outer blocks of trimethoxysilyl end-capped hyperbranched polyglycidol (HBPG/SiHBPG), of varying molecular weight, have been successfully synthesised and characterised. The effect of copolymer composition and structure upon the crystallization, melting, thermal degradation and aqueous solution behaviour were investigated at various temperatures. In aqueous solution, at concentrations above their corresponding critical aggregation concentration the PCL-HBPG/SiHBPG copolymers readily self-assemble into large multicore structures composed of PCL domains and corona consisting of HBPG/SiHBPG branches. The multicore structures were stabilized by numerous hydrogen-bonds from the HBPG moieties as well as via formation of siloxane crosslinks (i.e. SiOSi bonds). As the formation of the siloxane linkages is irreversible the PCL-HBPG/SiHBPG-based particles will be covalently crosslinked at higher concentrations in vivo and form injectable gels scaffolds that will be biocompatible and capable of invoking cell attachment and differentiation without the need for exogenous biological stimuli.

Supramolecular Synthon Approach in Designing Molecular Gels for Advanced Therapeutics

AbstractLow‐molecular‐weight gelators (LMWGs) are an important class of soft materials that offer various potential applications including drug delivery. Structural diversities of the reported LMWGs and lack of molecular‐level understanding of the self‐assembly process of gelation make it difficult to design a gelator a priori. Most often gelators are discovered in a serendipitous manner and second‐generation gelators are designed by modifying known gelling scaffolds. Since gel network within which the solvent molecules are immobilized is often found to be crystalline, a supramolecular synthon approach in the context of crystal engineering is demonstrated to be quite effective in designing LMWGs for various applications including therapeutics. Self‐drug‐delivery systems, wherein the need for a delivery vehicle does not exist, are becoming an effective alternative to conventional drug delivery systems. In the form of a simple gel (for non‐invasive topical application) or injectable gel (for invasive subcutaneous applications), LMWGs derived from drugs provide an effective way to develop self‐drug‐delivery systems. This review article encompasses the early development of LMWG research, describes gradual transition from discovering just a gelator to a gelator having potential material applications including drug delivery, and highlights the merit of supramolecular synthon approach in designing LMWGs for self‐drug‐delivery applications.

A sulfonated reversible thermal gel for the spatiotemporal control of VEGF delivery to promote therapeutic angiogenesis.

Despite medical and surgical advancements for the treatment of cardiovascular disease, mortality and morbidity remain high. Therapeutic angiogenesis has been one approach to address the major clinical need for a more effective treatment to restoring blood flow in ischemic organs and tissues, but current progress in angiogenic drug delivery is inadequate at providing sufficient bioavailability without causing safety concerns. An injectable sulfonated reversible thermal gel composed of a polyurea conjugated with poly(N-isopropylacrylamide) and sulfonate groups has been developed for the delivery of angiogenic factors. The thermal gel allowed for the spatiotemporal control of vascular endothelial growth factor release with a decreased initial burst release and reduced release rate in vitro. A subcutaneous injection mouse model was used to evaluate efficacious vascularization and assess the inflammatory response due to a foreign body. Thermal gel injections showed substantial vascularization properties by inducing vessel formation, recruitment and differentiation of vascular endothelial cells, and vessel stabilization by perivascular cells, while infiltrating macrophages due to the thermal gel injections decreased over time. These results demonstrated effective localization and delivery of angiogenic factors for therapeutic angiogenesis. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3053-3064, 2018.

Targeted Delivery and Controlled Release of a Small Molecule Matrix Metalloproteinase Inhibitor Using a Self-Assembling Hydrogel Following Myocardial Infarction

Background Strategic delivery of biomaterials to the newly formed myocardial infarction (MI) continues to be an area of active investigation and offers the opportunity to reappraise the use of small molecule therapeutics that hold high target specificity but are problematic when systemically delivered. The goal of this study was to examine the effects of late post-MI delivery (3 days post-MI) of a self-assembling hydrogel (SAgel), which had been loaded with a previously characterized matrix metalloproteinase inhibitor (MMPi). Hypothesis Using a minimally invasive (mini-thoracotomy) and an SAgel allowing for targeted myocardial injection array within the MI region of a large animal model as well as localized release of an MMPi, improved LV function and geometry would be demonstrated up to 28 days post-MI. Methods and Results MI was induced in adult pigs (25 kg) by left anterior descending (LAD) catheter balloon occlusion (90 min/then reperfusion) and at 3 days post-MI randomized to MI-SAgel/SD7300 (500 μg/mL; n=7) or saline (MI saline; n=8), whereby the injections were performed in a 9 point 100 uL array within the targeted LAD region. The SAgel adapts fluid-like properties to flow through the syringe (21 Gauge) due to shear forces during injection and rapidly reassembles with encapsulated SD7300 following injection into the MI region. LV ejection fraction (LVEF) and end-diastolic volume (LVEDV) were measured at Baseline (pre-MI) and at 14 and 28 days post-MI by echocardiography. LVEF fell post-MI but was significantly attenuated by SAgel/SD7300 injections. LVEDV increased from Baseline (35±2 mL) in the MI-saline (84+6) and MI-SAgel/SD7300 (64+4 mL groups at 28 days post-MI (p Conclusions This is the first study to demonstrate the feasibility of targeted delivery of a self-assembling injectable gel using a minimally invasive surgical approach at a relevant post-MI time point. Second, targeted delivery of this gel containing an MMPi for sustained local release demonstrated sustained beneficial effects on post-MI remodeling.

Precisely Tunable Sol-Gel Transition Temperature by Blending Thermoresponsive ABC Triblock Terpolymers.

Here, we report a facile methodology to control the sol-gel transition temperature (Tgel) of a physically cross-linked hydrogel by blending two kinds of ABC triblock terpolymers. Well-defined triblock terpolymers including thermosensitive N-isopropylacrylamide (NIPAAm), ABC1, and ABC2, were prepared by sequential reversible addition-fragmentation chain transfer polymerization. The chemical structure as well as the molecular weight of the A and B blocks for both polymers are identical, whereas the C blocks are different. The C block of ABC1 (C1) is a statistical copolymer of NIPAAm with hydrophobic n-butyl acrylate (BA), while that of ABC2 (C2) is a PNIPAAm homopolymer. Independently prepared ABC triblock terpolymer solutions exhibit well-defined sol-gel transitions. The Tgel of ABC1 is lower than that of ABC2 since hydrophobic BA is copolymerized into block C1. Remarkably, the Tgel varies linearly within this temperature range by simply blending the two polymers, while the resultant gel strength (∼G') remains almost unchanged. Therefore, the Tgel can be precisely adjusted by the mixing ratio of the two polymers. This method for straightforward manipulation of Tgel has great potential for various soft material applications such as biomaterials for tissue engineering, drug delivery systems, and injectable gels.