A functionalizable reverse thermal gel based on a polyurethane/PEG block copolymer

Park, Dae‐Won; Wu, Wei; Wang, Yadong

doi:10.1016/j.biomaterials.2010.09.044

Cited by 88 publications

(86 citation statements)

References 63 publications

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“…Previously, we have demonstrated that an aqueous solution of ESHU will undergo a sol-to-gel phase transition when the temperature is increased from room to body temperature, making it attractive for minimally invasive applications. 18 We hypothesized that ESHU would be a suitable platform for intraocular drug delivery and demonstrated that it is compatible with cells from ocular sources, and capable of releasing bevacizumab over a 17-week period in vitro. 19 The aim of the present study was to demonstrate sustained bevacizumab release in vivo when compared to a standard, bolus injection.…”

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confidence: 99%

Biocompatible Reverse Thermal Gel Sustains the Release of Intravitreal Bevacizumab In Vivo

Rauck

Friberg

Mendez

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. We assessed the in vivo release profile of bevacizumab from and biocompatibility of poly(ethylene glycol)-poly-(serinol hexamethylene urethane), or ESHU, a thermoresponsive hydrogel administered intravitreally for drug delivery.METHODS. The technical feasibility of injection was assessed quantitatively via mechanical testing. For in vivo studies, New Zealand White rabbit eyes were injected intravitreally with 0.05 mL of either: ESHU dissolved in 25 mg/mL bevacizumab, ESHU dissolved in PBS, or 25 mg/mL bevacizumab. Clinical examination included IOP measurements and examination with indirect ophthalmoscopy for signs of inflammation. Additionally, eyes were examined histologically following euthanasia. To quantify bevacizumab release, aqueous humor samples were obtained via anterior chamber paracentesis and ELISA was used to determine the concentration of drug weekly. In vitro cytotoxicity testing also was performed using bovine corneal endothelial cells. RESULTS.The ESHU was injected easily through a 31-gauge needle, was well tolerated in vivo, and caused minimal cell death in vitro when compared to other common materials, such as silicone oil. The long-term presence of the gel did not affect IOP, and there was no evidence of inflammation histologically or through indirect observation. The ESHU sustained the release of bevacizumab for over 9 weeks and maintained a drug concentration that averaged 4.7 times higher than eyes receiving bolus bevacizumab injections.CONCLUSIONS. To our knowledge, this is the first report demonstrating sustained bevacizumab release in vivo from an intravitreally injected hydrogel formulation, suggesting that this delivery system may be a promising candidate for ocular drug delivery.Keywords: thermally responsive hydrogel, ocular drug delivery, sustained release, biocompatibility, injectable gel C horoidal neovascularization (CNV) is the hallmark of many blinding disorders, most notably wet age-related macular degeneration (AMD) and diabetic retinopathy. It is characterized by pathologic blood vessel growth, which originates in the choroid and progresses through the Bruch's membrane into the subretinal space.1 These vessels are fragile and permeable, causing hemorrhage, retinal detachment, scarring, and ultimately, loss of central vision. Elevated levels of VEGF is a central cause of CNV.2-4 Thus, intravitreal injection of anti-VEGF medications, such as bevacizumab (Avastin) or ranibizumab (Lucentis), has emerged as a leading treatment strategy. [5][6][7] The efficacy of these drugs, however, is limited severely by rapid clearance from the eye; their half-lives are on the order of 7 days. 8,9 This necessitates frequent injections, imposing a significant burden on patients and increasing healthcare costs as well as procedure-related complications, such as endophthalmitis, retinal detachment, cataract, and uveitis.10-13 Therefore, a delivery system that extends the presence of intravitreal drugs in the eye is highly desirable for reducing injection frequency and adverse effects, w...

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confidence: 99%

Biocompatible Reverse Thermal Gel Sustains the Release of Intravitreal Bevacizumab In Vivo

Rauck

Friberg

Mendez

et al. 2014

Invest. Ophthalmol. Vis. Sci.

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“…This is an attractive property, especially for drug delivery, because it allows for controlled degradation. Another quality is that PEG gels can be modified to be thermally activated so that they are liquid at room temperature but quickly gel in situ [118] . Due to its hydrophilic properties, PEG has been useful in repairing damaged neuronal membranes when applied directly to the injury site immediately following a crush injury [119][120][121][122] , in a delayed application [123] , or as a subcutaneous application [124] .…”

Section: Poly-ethylene-glycol (Peg)/poly-ethylene Oxide (Peo)mentioning

confidence: 99%

“…PEG is favorable as it is functionalizable and groups have incorporated cell-binding domains such as RGD [125] and iKVAV [126] . it can be used for cell immobilization [127] and drug release [128] .…”

Section: Poly-ethylene-glycol (Peg)/poly-ethylene Oxide (Peo)mentioning

confidence: 99%

“…Another quality is that PEG gels can be modified to be thermally activated so that they are liquid at room temperature but quickly gel in situ [118] . Due to its hydrophilic properties, PEG has been useful in repairing damaged neuronal membranes when applied directly to the injury site immediately following a crush injury [119][120][121][122] , in a delayed application [123] , or as a subcutaneous application [124] .PEG is favorable as it is functionalizable and groups have incorporated cell-binding domains such as RGD [125] and iKVAV [126] . it can be used for cell immobilization [127] and drug release [128] .…”

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Biomaterials for spinal cord repair

Haggerty

Oudega

2013

Neurosci. Bull.

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Spinal cord injury (SCi) results in permanent loss of function leading to often devastating personal, economic and social problems. A contributing factor to the permanence of SCi is that damaged axons do not regenerate, which prevents the re-establishment of axonal circuits involved in function. Many groups are working to develop treatments that address the lack of axon regeneration after SCi. The emergence of biomaterials for regeneration and increased collaboration between engineers, basic and translational scientists, and clinicians hold promise for the development of effective therapies for SCi. A plethora of biomaterials is available and has been tested in various models of SCi. Considering the clinical relevance of contusion injuries, we primarily focus on polymers that meet the specific criteria for addressing this type of injury. Biomaterials may provide structural support and/or serve as a delivery vehicle for factors to arrest growth inhibition and promote axonal growth. Designing materials to address the specific needs of the damaged central nervous system is crucial and possible with current technology. Here, we review the most prominent materials, their optimal characteristics, and their potential roles in repairing and regenerating damaged axons following SCi.Keywords: spinal cord injury; axon regeneration; biodegradable materials; extracellular matrix proteins; functional recovery; growth factor; guidance; injury and repair; spinal motor neuron IntroductionSpinal cord injury (SCi) causes loss of neurons and axons resulting in motor and sensory function impairments. There are thousands of new cases of SCi in the world annually [1,2] occurring often in young adults. The lack of endogenous repair and the significant costs to the individual, family and society [1] are important motivations behind the continuing efforts to develop effective therapies. Promoting axonal regeneration is considered a potential repair strategy because it could lead to recovery of axonal circuits involved in motor and/or sensory function [3] .The central nervous system (CNS) neurons are intrinsically capable of some regeneration of damaged axons [4] but their attempts after SCi are frustrated by structural and chemical obstructions in the damaged nervous tissue [5] . Spinal cord repair approaches typically lead to small functional gains. one feature that most of these approaches have in common is a poor axonal regeneration response, suggesting that promoting axonal regeneration, including synapse formation, is essential to achieve substantial functional repair after SCi. if so, it is rational to anticipate that effective spinal cord therapies will need to include interventions addressing the axon growth-inhibition that leads to the poor axonal growth responses. As introduced above, axonal regeneration is considered an important repair mechanism for the injured spinal cord. Therefore, this review focuses on materials that have shown most promise to elicit an axonal regeneration response to foster functional restoration after ...

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“…Biodegradable polyurethanes can be engineered into different physical forms as drug carriers, such as nanoparticles (Wang, Gao et al 2013), microspheres (Subhaga, Ravi et al 1995), micelles (Yu, Ding et al 2014), films ), gels (Park, Wu et al 2011), or scaffolds (Hafeman, Zienkiewicz et al 2010). Therapeutic agents can be loaded into these formulations by many methods, such as casting, oil-in-water emulsion/solvent evaporation, covalent link to polyurethane chains and adsorption.…”

Section: Biodegradable Polyurethanes As Drug Delivery Systemsmentioning

confidence: 99%

Delivery of therapeutic peptides from thermoplastic polyurethane films

Zhang¹

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Thermoplastic polyurethanes (TPUs) are widely used in biomedical applications due to their excellent mechanical properties and biocompatibility. Their roles as matrices to incorporate therapeutics have been investigated in different areas. With the advance of peptides as therapeutics, there is critical need for investigating delivery of peptides using drug delivery systems. However, there is little work on understanding the release of peptides from TPUs. The aim of this study is to understand how therapeutic peptides might be incorporated and released from TPUs.Initially, we compared the effect of supercritical carbon dioxide treatment and solvent casting on the loading and release of model drugs from polyurethane films. We found that scCO2 treatment may cause a shift of hard segment to the surface of film, but this treatment did not significantly affect physical properties of TPUs. This rearrangement of hard segment caused by scCO2 may affect drug release. We then examined the loading and release of 3 model drugs using scCO2 and compared with solvent casting. ScCO2 was able to load all these 3 model drugs consistently and homogeneously into the films, and the release of these 3 drugs was qualitatively similar by scCO2 or solvent casting.However, the amount of drug accumulated in the films by scCO2 was much less than the total amount of drug in the reaction vessel. This could be a practical limitation for therapeutics such as peptides that are expensive to synthesise. In addition, we found the composition of hard and soft segments may contribute greatly to the efflux of drugs.On the basis of these results, we next investigated the in vitro efflux of peptides from polyurethane films by solvent casting. Interestingly, we found there was a correlation between cumulative release and molecular weight of the peptides. Because one of the causes of implant failure is localised inflammation, we were specifically interested in the delivery of C5aR antagonists from TPU films. First, we found that cyclic peptides may be more stable under harsh casting conditions (elevated temperatures, organic solvents) compared to the linear peptides. Mild conditions are required to retain the bioactivity of peptides. Interestingly, similar to the efflux results of model drugs, the release profiles of peptides were also dependent on the composition of hard and soft segments of TPUs. We also found serum proteins in the medium could facilitate the release of peptides. In addition, in vitro bioactivity of the released peptides was examined by measuring intercellular Ca 2+ concentration mobilization in a cell model of C5a receptor signaling. The ii results demonstrate that released peptides retained their bioactivity. To better control the efflux of peptides, we examined blending of different TPUs. We found that the initial rate and extent of drug released from Tecoflex 80A was significant suppressed by increasing the amount of ElastEon 5325 in the blend. These results offer a simple approach for controlling drug release from TPUs.Furt...

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A functionalizable reverse thermal gel based on a polyurethane/PEG block copolymer

Cited by 88 publications

References 63 publications

Biocompatible Reverse Thermal Gel Sustains the Release of Intravitreal Bevacizumab In Vivo

Biocompatible Reverse Thermal Gel Sustains the Release of Intravitreal Bevacizumab In Vivo

Biomaterials for spinal cord repair

Delivery of therapeutic peptides from thermoplastic polyurethane films

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