316

http://journals.tubitak.gov.tr/biology/

Turkish Journal of Biology Turk J Biol(2016) 40: 316-326© TÜBİTAKdoi:10.3906/biy-1507-143

Controlled nitric oxide release for tissue repair and regeneration

Yan NIE1, Zongjin LI1,2,*

1Nankai University School of Medicine, Tianjin, P.R. China2The Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin, P.R. China

* Correspondence: zongjinli@nankai.edu.cn

1. IntroductionNitric oxide (NO), first identified as a gaseous signaling molecule and initially called endothelium-derived relaxing factor (Ignarro et al., 1987), is generated from L-arginine by constitutive NO synthase (cNOS) or inducible NO synthase (iNOS) (Marletta, 1993). As a highly reactive radical, NO has been demonstrated as an essential molecule that regulates cellular/molecular functions in mammals and plays vital roles in numerous physiological systems, such as the cardiovascular, respiratory, nervous, and immune systems, as well as biological processes associated with tissue regeneration and cancer development (Carpenter and Schoenfisch, 2012; Gao et al., 2013). Deficiency of NO is associated with a number of pathologies, such as nonhealing chronic wounds, ischemic diseases, and carcinogenesis (Stone et al., 2012; Nguyen et al., 2013; Rybinski et al., 2014; Singh and Singh, 2015). Thus, supplying exogenous NO could be a possible and efficient method for treating these kinds of diseases. However, an exogenous NO supply is inconvenient, especially considering its extremely short half-life and the rapid loss of its bioactivity. Besides, the therapeutic effects of NO on physiology are concentration-dependent (Diers et al., 2011; Inoue et al., 2011; Wang et al., 2014), and

how to sustain NO levels in an optimum range is another challenge facing NO-based therapy in clinical application.

In response to the need for controlled NO release for therapeutic application, a chemically modified NO delivery system that is capable of storing NO in a relatively inert state and releasing NO in a controlled manner could be a viable solution (Zhang et al., 2012). In this review, we will focus on the recent advances in controllable NO release systems and therapeutic application of NO for tissue repair and regeneration. Moreover, the therapeutic mechanisms and theranostic applications of tunable NO release in translational medicine will be discussed.

2. Controllable NO release systems Glyceryl trinitrate (GTN), also known as nitroglycerin, has been widely used for decades to treat heart disease (Agvald et al., 2002). However, many unwanted side effects, such as headaches, endothelial dysfunction, and enzymatic tolerance, caused by the application of GTN have been reported and uncontrolled NO release is one of the culprits for these side effects (Ghaffari et al., 2006). Thus, releasing NO on demand will be of the utmost importance for developing superior therapies for various diseases caused by inadequate endogenous NO production. The advancements

Abstract: The discovery that nitric oxide (NO) plays crucial roles in mammalian systems has spurred considerable interest in its translational application. However, the major problem with its application in clinical settings is the high reactivity of NO, which makes it difficult to supply NO with spatiotemporal accuracy while maintaining its bioactivity. To deliver NO at a specified rate to a preferred location for a precise period of time is highly demanded. The significant technological advancements in controlled release make it possible to control NO release at the target site with a sustained release rate and an optimum concentration, and then provide a longer therapeutic duration of NO. Moreover, biomaterials designed for regenerative applications provide carriers with support structures for controlled NO releasing. Meanwhile, engineered matrices with controlled NO release have been used as vehicles for stem cell delivery to enhance cell engraftment and further to improve therapeutic effects of transplanted cells. In this review, we will provide an overview of controlled NO release materials, as well as the mechanisms of their treatment effects in tissue-repairing processes. Furthermore, the application of on-demand NO-releasing materials as carriers for stem cell transplantation and the NO-based therapeutic applications in translational medicine will be discussed.

Key words: Nitric oxide, controlled release, biomaterial, stem cell, regenerative medicine

Received: 30.07.2015 Accepted/Published Online: 17.11.2015 Final Version: 23.02.2016

Review Article

NIE and LI / Turk J Biol

317

of controlled-release technology have made it possible to harness NO release at a targeted site with an optimum concentration-versus-time profile, which provides a longer therapeutic duration of action and optimizes the therapeutic effects of NO (Quinn et al., 2015). Numerous controlled NO-releasing materials have been designed with the aim of masking undesirable drug properties, which provided us with useful tools to evaluate the pivotal role of NO in mammalian systems (Maruhashi et al., 2014). 2.1. Nonenzymatic activated NO release The prodrug strategy provides an alternative approach to convert pharmacologically inert derivatives into active drug molecules in vivo by external stimuli (Kitamura et al., 2014; Neidrauer et al., 2014). Among these, light- or humidity-manipulated NO-releasing systems provide easily adjustable parameters (e.g., wavelength, duration, and relative intensity) to regulate NO release (Wu and McGinity, 2000; Sortino, 2012; Bajpai et al., 2015; Chiang et al., 2015).

A series of NO-releasing substances that could be photolyzed by light irradiation with wavelengths ranging from ultraviolet (UV) light (Namiki et al., 1999; Hiramoto et al., 2001) to visible light (Ostrowski et al., 2012; Hitomi et al., 2014) to near-infrared (NIR) light (Eroy-Reveles et al., 2008; Hishikawa et al., 2009) were reported in numerous studies. Biocompatible polymers and photochemical NO-releasing complexes were used to form a composite material, trans-Cr(cyclam)(ONO)2+ (CrONO), which could release NO for more than 30 h after visible light irradiation (Mase et al., 2015). Another frequently used NO donor, S-nitroso-N-acetyl-D penicillamine (SNAP), was covalently linked to polydimethylsiloxane (PDMS), which endowed SNAP with the ability of spatiotemporally controlling NO release (Romanowicz et al., 2013).

Moisture-responsive polymers have been investigated broadly in the context of drug delivery because of their fast and ongoing response to humidity and the easy manipulation for accomplishing precise control of NO release (Lowe et al., 2012; Liu et al., 2015). Recently, increasing attention has been paid to the application of zeolites, three-dimensional microporous crystalline aluminosilicates, as media for delivering low-molecular-weight bioactive substances. With polylactic acid (PLA) encapsulation, zeolite A had the ability to incorporate NO under dry conditions and release NO with the only requirement of moisture (Liu and Balkus, 2009). In addition, the rate of NO release can be easily handled and manipulated by altering the PLA fiber porosity. Analogously, melt-spun fiber also had the capability of binding NO adducts, such as diazeniumdiolates (NONOates) (Lowe et al., 2012). In order to manipulate NO release, the fiber is dipped in biodegradable polycaprolactone (PCL) to create a porous coating on its surface. With the degradation of

the coated materials, the fiber complex could replicate the natural production of NO upon exposure to humidity.2.2. Enzymatic activated NO release For enzyme-activated NO generation, NO donors are blocked by protecting groups to prevent uncontrollable NO release, and the inactivated donors are often loaded on a precursor compound that is used as a reservoir or matrix for both controlled release of NO and delivery of NO (Clas et al., 2014). Prodrug-activating enzymes are employed to remove the protecting groups from these parent drugs, which will lead to the release of active NO.

The most commonly used NO-releasing drugs are nitrate esters, which can utilize different endogenous hydrolytic enzymes to achieve bioconversion and NO release (Napoli and Ignarro, 2003). A series of ester-based NO-releasing derivatives possessing 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate or 1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate moiety were synthesized (Velázquez et al., 2005). All these compounds could release NO by incubation with porcine liver esterase in a lower range (16.3%–19.2%). An improved NO release profile was observed after incubation with nonspecific esterases presented in serum (81.6%–93.6% range).

Glycosylation modification is another commonly used approach to achieve tunable NO release. In this method, galactose is utilized as a protective moiety to block NO release from the NO-storing medium; β-galactosidase is added to remove the protective group, which would finally be able to initiate NO release in a controlled manner (Figure 1) (Zhao et al., 2013). Two β-galactosidase-responsive NO-releasing hydrogels were reported recently (Gao et al., 2013; Zhao et al., 2013). Adding β-glycosidase to remove the sugar-capping group could lead to controllable NO release. The rate of NO release could be modulated by fine-tuning the concentration of β-glycosidase, which could provide a convenient method to modulate NO release and maintain the bioavailability of NO.2.3. Multifunctional NO-releasing systemRecent advances in nanoparticle engineering are creating new opportunities for the development of multifunctional nanoparticles for NO delivery. Multifunctional systems that integrate different functionalities in a coordinated and organized manner are capable of accommodating a combination of therapeutic agents with different properties, such as imaging and specific targeting. Therefore, a targeted and traceable therapeutic strategy combined with delivery NO and imaging probes provides a versatile platform that can potentially enhance the therapeutic efficacy of NO in regenerative medicine (Hetrick et al., 2009). 2.3.1. Real-time monitoring of controlled NO release Over the past years, nanotechnology has developed rapidly and has been employed for disease diagnosis and treatment. Nanoparticles conjugated with NO-releasing

NIE and LI / Turk J Biol

318

moiety, having both diagnostic and therapeutic functions in a single integrated system, will improve and expand a more personalized, customized treatment model based on molecular-level diagnosis (Chen et al., 2013; Yang et al., 2013). Several elaborately designed NO-releasing and imaging nanoparticle products, which could achieve the objectives of maintaining the potency of NO and further exploring the mechanism of tissue repair, early diagnosis, and simultaneous monitoring of therapeutic effect and timely adjustment of therapy regimen in the context of tracing NO delivery, have been invented as tools for theranostic nanomedicine (Rizzo et al., 2013; Ryu et al., 2014). A chitosan nanosphere, which was exploited as a

vehicle of a photoresponsive NO-releasing complex, was conjugated with fluorescent agents (Tan et al., 2013). The incorporation of NO-containing materials and NIR fluorescent quantum dots gave this chitosan-based agent the capability of releasing NO in a controllable fashion and monitoring the NO release in situ. The wavelength of excitation for NO release was much shorter than that of fluorescent lights emitted from the compound, and thus no mutual interferences would appear. Researchers further developed two other compounds with the competence of effective NO release and excellent properties of optical imaging, which could be promising agents for theranostics (Figure 2) (Tan et al., 2013, 2014).

Figure 1. The pattern of enzyme-activated nitric oxide (NO) release. The on-demand release of NO is achieved by controlling the decomposition process of the NO-containing compound (chitosan-NO polymer), which is blocked by a protecting moiety (galactose). NO release only occurs after β-glycosidase removes the galactose-capping group. Reprinted with permission from Elsevier (Zhao et al., 2013).

NIE and LI / Turk J Biol

319

2.3.2. Site-specific delivery of controlled NO-releasing agentA major issue associated with NO donors is to stabilize and release NO locally and directly in different tissues. Macromolecules, such as dendrimers, hydrogels, polymers, and nanoparticles, have been used and exhibit exceptional potential in directly delivering NO in a controlled spatial and temporal manner with superior biocompatibility for pharmacological applications. The NO-donating agent [Ru(terpy)(bdqi)NO](PF6)3, with the ability of controlled release of NO upon photoirradiation, was loaded onto nanoparticles, which endowed the NO donor with an epidermal targeting effect (Marquele-Oliveira et al., 2010). Photochemical studies confirmed that light irradiation could be employed to control NO release and improve NO concentration in skin. Likewise, the controlled NO-releasing dendrimers, which were capable of selectively targeting inflamed endothelium, showed significant therapeutic potential for reducing ischemia/reperfusion injury (Johnson et al., 2010).

Improving the specificity is a major goal of gene-directed enzyme prodrug therapy. Exogenous genes that encode cell/tissue-specific enzymes, such as nitroreductase (Sharma et al., 2013), β-lactamase (Yepuri et al., 2013), glutathione-S-transferase (GST) (Weyerbrock et al., 2012), and β-galactosidase (Chen and Zhang, 2013), are employed to achieve NO release at target sites. A bacterial biofilm-targeted NO-releasing agent was designed with the

capability of selectively releasing NO upon contact with enzyme β-lactamase (Yepuri et al., 2013). The location-specific NO release could minimize the interruption of NO-associated side effects in normal tissue. Likewise, an Escherichia coli nitroreductase (NTR)-activated NO prodrug also had the ability of site-directed release of NO (Sharma et al., 2013); the derivative of the commonly used NO donor, diazeniumdiolate (NONOate), could not release NO until it was metabolized by β-galactosidase-expressing cells (Chen and Zhang, 2013). Moreover, O2-(2,4-dinitrophenyl)1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K), a site-specific NO-releasing compound that could be activated in glutathione (GSH)-expressing cells, showed improvement in duration time and treatment efficacy (Weyerbrock et al., 2012).

3. Mechanism for therapeutic effects of controlled NO releaseNO is involved in diverse processes, such as responding to oxidative stress and inflammation, controlling blood flow, and regulating the proliferation and differentiation of cells. Administration of exogenous NO to elevate NO levels has been recognized as a strategy for tissue regeneration. Increasing evidence suggests that NO is a key mediator in different phases of tissue reparative processes, including collagen deposition (Han et al., 2012), fibroblast migration (Han et al., 2012), and angiogenesis (Kazakov et al., 2012; Most et al., 2013).

Figure 2. Dual functional agent with the ability of controlled release and imaging of NO. (a) Synthetic strategy to produce GSH-capped Ag2S quantum dots (QDs); (b) synthetic strategy and light-triggered NO release mechanism of NIR fluorescent Ag2S QDs@CS-RBS nanospheres; (c) NIR imaging excited by a 785-nm laser; (d) visible fluorescence imaging excited by 488-nm laser of a nude mouse at 10 min after subcutaneous injection of Ag2S QDs@CS-RBS nanospheres and CuFL; (e) in a control experiment, a nude mouse was imaged under irradiation of 488-nm laser at 10 min after subcutaneous injection of CuFL alone. Reprinted with permission from the Royal Society of Chemistry (Tan et al., 2014).

NIE and LI / Turk J Biol

320

3.1. Promoting angiogenesisStimulating angiogenesis is a promising therapeutic strategy for tissue defects, because nutrients, oxygen, and cytokines transported by blood vessels are of essential importance for normal tissue function (Wang et al., 2015; Zhao and Li, 2015). Resuming the blood stream to the damaged area is a prompt, straightforward, and effective method for tissue repair. NO and NO-involving signaling pathways could promote angiogenesis, which was demonstrated as a vital step in wound healing (Luo and Chen, 2005; Chin et al., 2011) and ischemic disease recovery (Alkasaki et al., 2004; Kumar et al., 2007). Supplementation of exogenous NO in a controlled fashion could modulate the related biological processes and further promote angiogenesis at the site of injury (Namkoong et al., 2008). Recently, a study was performed to compare the proangiogenic potential of six different NONOate-based NO-releasing agents in a chicken embryo partial ischemia model (Majumder et al., 2014). The results showed that different platforms had different NO-releasing patterns and performed their functions in different periods of angiogenesis. In this model, spermine NONOate (SP) exhibited the best angiogenic effect among these NONOate-based compounds, which highlighted the necessity of using the most suitable NO-releasing system during specific phases of tissue regeneration. 3.2. Enhancing efficacy of stem cell-based therapyStem cell-based therapy has achieved successful therapeutic effects in experimental and clinical investigations in the past few decades, which provides great hope for the treatment of a wide variety of life-threatening diseases. However, the low rates of cell engraftment, viability, and retention limit the application of stem cell therapy (Li et al., 2009a, 2009b, 2009c; He et al., 2015; Yao et al., 2015). Because of these obstacles, developing methods for alleviating cell apoptosis may be of the utmost importance for stem cell therapy. Moreover, altering stem cell fate (e.g., coaxing pluripotent stem cells into committed progenitor lineages) for therapeutic applications is a feasible and safe strategy that can minimize the risk of cellular misbehavior (Li et al., 2008, 2009a, 2009b, 2009c; Su et al., 2011).

NO could participate in regulating cell proliferation, differentiation, and migration, acting as an important gaseous signaling molecule (Fuseler and Valarmathi, 2012; Curtis et al., 2014). NO was capable of favoring tissue regeneration by enhancing self-renewal ability and inhibiting the maldifferentiation of mesenchymal progenitors (Buono et al., 2012; Cordani et al., 2014). Evidence has also been provided to demonstrate that NO could promote the differentiation of mesenchymal stem cells (MSCs) into endothelial cells, which was also a promising strategy for tissue repairing. In a recent study, bone marrow multipotent progenitor cells (MAPCs) were cultured with two kinds of NO-releasing agents, NONOate

and sodium nitroprusside (SNP). Under a sustained NO-releasing environment, increased levels of von Willebrand factor (vWF) mRNA and protein were found, which indicated the endothelial differentiation of MAPCs (Chu et al., 2008).

Utilizing synthetic biomaterials as vehicles for in vivo transplantation of stem cells has been demonstrated as a promising strategy for increasing the retention and survival rate of administrated stem cells. These biomaterials could not only act as a scaffold for cell anchorage but could also provide a supportive niche for cell engraftment (Li et al., 2009a, 2009b, 2009c; He et al., 2015). A recent study developed a peptide hydrogel, which could release NO in a controllable manner catalyzed by β-galactosidase, together with MSCs for myocardial infarction treatment (Yao et al., 2015). Those results revealed that the NO released from the hydrogel could significantly enhance the engraftment and paracrine effect of MSCs. Cotransplantation of MSCs with NO-releasing hydrogel could lead to better outcomes of blood vessel reconstruction and heart performance after myocardial infarction through the NO-activated VEGF/VEGFR2 pathway in a mouse myocardial infarction model (Figure 3) (Yao et al., 2015).3.3. Antimicrobial property of NOWound infection remains a serious threat to patients worldwide. A certain degree of antimicrobial property of NO has been applied against pathogen invasion (Hetrick et al., 2009). A probiotic bacteria-based system that controlled the production of NO gas (gNO) by the metabolism of lactic acid bacteria in an adhesive gas-permeable membrane was offered to treat dermal wounds (Jones et al., 2012). In that study, an infected full-thickness dermal wound model was used to evaluate the preclinical efficacy of this novel patch. Over 21 days of therapy, wound closure in the gNO-producing patch-treated groups was significantly increased based on the antimicrobial activity of NO.

4. Controlled NO release for tissue regenerationMounting evidence indicates that an appropriate concentration of NO at the injury site is favorable for tissue repair, while deficient endogenous NO production could hamper the recovery process (Oplander et al., 2012). Exogenous supplementation of NO could be the best way to cope with the problem of NO deficiency. Curative effects showed that localized and well-timed NO replenishing in an on-demand manner could be a superior strategy to promote tissue repair compared to spontaneous NO release. 4.1. NO therapy for cardiovascular diseasesCardiovascular disease (CVD) remains the leading cause of death and morbidity in the world (He et al., 2015; Yao et al., 2015; Zhao and Li, 2015). The nonsurgical treatment

NIE and LI / Turk J Biol

321

of cardiac therapy has been proven to be a low-risk and high-efficiency treatment option for cardiac patients by restoring oxygenated blood flow back to the heart and other organs of the body (Fang et al., 2013). Extensive experimental and clinical investigations have revealed the association between vascular NO and cardiovascular disease (Rochette et al., 2013). Reduced NO production and impaired NO bioavailability are the common causes of cardiovascular diseases.

In cardiovascular disease therapy, NO is recognized as a unique reactive modulator involved in vascular function during tissue ischemia. The NO donor SNAP has showed cardioprotective effects. However, a high dosage of SNAP was required to obtain this therapeutic effect, which was toxic to cells. To tackle this issue, SNAP was conjugated with polyamidoamine dendrimers with large drug payloads. Minimized dosage of SNAP and a better curative efficacy for reducing infarct size and ischemia/reperfusion

injury were obtained by the triggering of GSH (Johnson et al., 2010). Additionally, conjugation to chemically modified micromolecules could confer the capability of tissue selectivity to NO donors, which has demonstrated good therapeutic effect in the ischemia/reperfusion injury model. A new type of S-nitrosothiol-based macromolecular NO-releasing complex, mannosylated (Man)-poly SNO-bovine serum albumin (BSA) and galactosylated (Gal)-poly SNO-BS, was designed and synthesized (Katsumi et al., 2009). These complexes made it possible to target NO delivery in the compromised tissue and prolong the retention of NO donors in the systemic circulation. NO released from these macromolecules restored proper circulation after a period of restricted blood flow.

After myocardial infarction, apoptotic and necrotic cardiomyocytes are progressively replaced by fibroblast-like cells, which lead to the impairment of cardiac function. Stem cell therapy is a new therapeutic

Figure 3. NapFF-NO hydrogel enhances the therapeutic effect of AD-MSCs for myocardial infraction. Encapsulation of AD-MSCs by NapFF-NO hydrogel could prevent transplanted cells effusing from injection positions. NO molecule released from NapFF-NO hydrogel catalyzed by β-galactosidase had the ability to facilitate angiogenic cytokine secretion of AD-MSCs, resulting in promoting angiogenesis, AD-MSC survival, and cardiac function. Reprinted with permission from Elsevier (Yao et al., 2015).

NIE and LI / Turk J Biol

322

approach for repopulating damaged myocardium via cell transplantation (Li et al., 2009a, 2009b, 2009c; Yao et al., 2015). Despite this, the beneficial effects of transplanted cells are limited due to low retention of these cells during the early posttransplantation period (Du et al., 2015; He et al., 2015). Transplantation of stem cells in biomaterials to produce better retention and engraftment in the infarcted heart has been widely reported. Transplantation MSCs with controllable NO-releasing hydrogel exhibited relatively high effects on heart function improvement, which could be attributed to the hydrogel-enhanced cell engraftment and survival and the NO-promoted angiogenesis and blood vessel reconstruction in ischemic myocardium (Yao et al., 2015).4.2. Tunable release of NO for wound healing Patients suffering from chronic wounds and impaired healing conditions will become even more burdensome in both human health and economic terms (Eming et al., 2014). Innovative therapies for treating unhealed wounds or for speeding up the repair of acute wounds and maximal restoration of tissue function are needed. Topical application of therapeutic agents combined with controlled NO release have provided a safe, efficient, and feasible remedy for treating these lesions without interrupting normal tissues (Oplander et al., 2013).

The therapeutic effects exhibited by NO are in connection with its concentration (Burke et al., 2013), release time, and cell types (Fleissner and Thum, 2011; Krause et al., 2011). It is absolutely vital to deliver NO to the target area in a well-contained manner, for excessive amounts of NO could pose a greater risk of injury to certain tissues. Nanoparticle-based drug delivery systems have been broadly used as a promising method to improve the efficacy of existing drugs with the ability to achieve increased therapeutic duration, enhanced bioavailability, and controlled drug release (Probst et al., 2013). Conjugating NO donors to nanoparticles (NO-NPs) could significantly increase the therapeutic effect of NO. In different treatment groups, skin-injured mice were respectively treated with NO-NPs, nanoparticles without NO, and DETA NONOate (Blecher et al., 2012). In the treated groups, the wound area in NO-NP-treated mice decreased by 29.4% compared to 1.9% in nanoparticle-treated mice and 2.3% in DETA NONOate-treated mice, which showed higher therapeutic efficiency of controlled NO release compared to the group with spontaneous NO release. Likewise, the treatment effect of another kind of NO-NP during the wound repair process was evaluated (Han et al., 2012). The NO level was increased in the NO-NP-treated group compared to the nanoparticle-treated group and the untreated control group. A high wound closure rate was obtained and complete wound closure was achieved only in the NO-NP-treated group.

Ordinary bandage dressings are widely used in wound management with certain advantages. Combined with NO-releasing technology, several fabrics and bandages have been applied in medical practice and exhibited a greater potency to accelerate wound healing. Comparing topical application of NO-releasing films with an extremely short period, erythema disappeared and an increasing rate of blood flow was obtained (Marcilli and de Oliveira, 2014). Likewise, applying electrospinning technology, humidity-sensitive NO-releasing bandages and dressings were developed and assessed (Lowe et al., 2015). The wound healing rate of the NO-treated groups was significantly faster than that of the control group. Additionally, the average capillary density in the NO-treated group was about 60% higher than that of the control group.

NO-releasing sutures hold promise in treating injury located in deep tissue. PCL-coated melt-spun acrylonitrile-based sutures could release NO continually (Lowe et al., 2014). NO could be released from the sutures after they were exposed to moist environments. With PCL coating, the NO release process could be prolonged, which could prevent infection and promote wound healing.4.3. Controlled NO release to injured tendon and muscle Tendon and muscle injuries are common, which result in billions of dollars in health care expenses. NO is a function-preserving and repair-stimulating mediator in injury and disease, which has been demonstrated to have great therapeutic potency in both tendinopathies and muscle injuries, for it is remarkably effective for preserving function and stimulating repair of the injured tissue (Murrell et al., 2008; De Palma et al., 2014).

Addition of NO through nitric oxide-paracetamol could enhance tendon healing by improving collagen content and organization in damaged tendons (Murrell et al., 2008). In a cGMP-dependent pathway, NO was capable of stimulating the proliferation of satellite cells, which are critical to sustain muscle regeneration during numerous rounds of damage (Kuang et al., 2008). It has been demonstrated that the enhanced self-renewal ability of satellite cells induced by treatment with the NO-donating drug molsidomine was sufficient to increase the number of satellite cells during repetitive acute and chronic damages and favored muscle regeneration (Buono et al., 2012). NO-based therapy also exhibited the ability of enhancing the regenerative potential of the damaged muscle by inhibiting the maldifferentiation of mesenchymal fibroadipogenic progenitors into adipocytes (Cordani et al., 2014).

5. Summary The current existing controllable NO-releasing systems have gradually demonstrated their superiority, such as the ease of manipulation, site specificity, longer duration of NO release, excellent biocompatibility, and reduced side

NIE and LI / Turk J Biol

323

effect profiles. Based on the understanding of therapeutic mechanisms, preliminary evaluations have showed that these NO-releasing agents have great potential for regenerative medicine and tissue engineering. Controlling the extent, rate, and time of NO release can be a very practical approach to optimize its performance. Moreover, the development of high-quality NO controlled-release formulations provides optimism for NO-releasing platforms for regenerative therapy.

AcknowledgmentsThis work was partially supported by grants from the National Natural Science Foundation of China (81371620, 81320108014), the National Basic Research Program of China (2011CB964903), and the Program for Changjiang Scholars and Innovative Research Team in University (IRT13023).

References

Agvald P, Adding LC, Artlich A, Persson MG, Gustafsson LE (2002). Mechanisms of nitric oxide generation from nitroglycerin and endogenous sources during hypoxia in vivo. Brit J Pharmacol 135: 373–382.

Alkasaki Y, Miyata M, Eto H, Shirasawa T, Hamada N, Ikeda Y, Biro S, Tei C (2004). Repeated thermal therapy upregulated endothelial nitric oxide synthase and augmented ischemia-induced angiogenesis in apolipoprotein E-deficient mice. Circulation 110: 305–305.

Bajpai S, Dehariya P, Singh Saggu S (2015). Investigation of moisture sorption, permeability, cytotoxicity and drug release behavior of carrageenan/poly vinyl alcohol films. J Macromol Sci A 52: 243–251.

Blecher K, Martinez LR, Tuckman-Vernon C, Nacharaju P, Schairer D, Chouake J, Friedman JM, Alfieri A, Guha C, Nosanchuk JD et al. (2012). Nitric oxide-releasing nanoparticles accelerate wound healing in NOD-SCID mice. Nanomed-Nanotechnol 8: 1364–1371.

Buono R, Vantaggiato C, Pisa V, Azzoni E, Bassi MT, Brunelli S, Sciorati C, Clementi E (2012). Nitric oxide sustains long-term skeletal muscle regeneration by regulating fate of satellite cells via signaling pathways requiring Vangl2 and cyclic GMP. Stem Cells 30: 197–209.

Burke AJ, Sullivan FJ, Giles FJ, Glynn SA (2013). The yin and yang of nitric oxide in cancer progression. Carcinogenesis 34: 503–512.

Carpenter AW, Schoenfisch MH (2012). Nitric oxide release: Part II. Therapeutic applications. Chem Soc Rev 41: 3742–3752.

Chen C, Zhang E (2013). β-Galactosyl-pyrrolidinyl diazeniumdiolate: an efficient tool to investigate nitric oxide functions on promoting cell death. Appl Microbiol Biotechnol 97: 7377–7385.

Chen Y, Chen HR, Shi JL (2013). In vivo bio-safety evaluations and diagnostic/therapeutic applications of chemically designed mesoporous silica nanoparticles. Adv Mater 25: 3144–3176.

Chiang WL, Lin TT, Sureshbabu R, Chia WT, Hsiao HC, Liu HY, Yang CM, Sung HW (2015). A rapid drug release system with a NIR light-activated molecular switch for dual-modality photothermal/antibiotic treatments of subcutaneous abscesses. J Control Release 199: 53–62.

Chin LC, Kumar P, Palmer JA, Rophael JA, Dolderer JH, Thomas GPL, Morrison WA, Penington AJ, Stewart AG, Mitchell GM (2011). The influence of nitric oxide synthase 2 on cutaneous wound angiogenesis. Brit J Dermatol 165: 1223–1235.

Chu L, Jiang Y, Hao H, Xia Y, Xu J, Liu Z, Verfaillie CM, Zweier JL, Liu Z (2008). Nitric oxide enhances Oct-4 expression in bone marrow stem cells and promotes endothelial differentiation. Eur J Pharmacol 591: 59–65.

Clas SD, Sanchez RI, Nofsinger R (2014). Chemistry-enabled drug delivery (prodrugs): recent progress and challenges. Drug Discov Today 19: 79–87.

Cordani N, Pisa V, Pozzi L, Sciorati C, Clementi E (2014). Nitric oxide controls fat deposition in dystrophic skeletal muscle by regulating fibro-adipogenic precursor differentiation. Stem Cells 32: 874–885.

Curtis BM, Leix KA, Ji YJ, Glaves RSE, Ash DE, Mohanty DK (2014). Slow and sustained nitric oxide releasing compounds inhibit multipotent vascular stem cell proliferation and differentiation without causing cell death. Biochem Bioph Res Co 450: 208–212.

De Palma C, Morisi F, Pambianco S, Assi E, Touvier T, Russo S, Perrotta C, Romanello V, Carnio S, Cappello V et al. (2014). Deficient nitric oxide signalling impairs skeletal muscle growth and performance: involvement of mitochondrial dysregulation. Skelet Muscle 4: 22.

Diers AR, Broniowska KA, Darley-Usmar VM, Hogg N (2011). Differential regulation of metabolism by nitric oxide and S-nitrosothiols in endothelial cells. Am J Physiol Heart Circ Physiol 301: H803–812.

Du W, Tao H, Zhao S, He ZX, Li Z (2015). Translational applications of molecular imaging in cardiovascular disease and stem cell therapy. Biochimie 116: 43–51.

Eming SA, Martin P, Tomic-Canic M (2014). Wound repair and regeneration: mechanisms, signaling, and translation. Sci Transl Med 6: 265SR6.

Eroy-Reveles AA, Leung Y, Beavers CM, Olmstead MM, Mascharak PK (2008). Near-infrared light activated release of nitric oxide from designed photoactive manganese nitrosyls: strategy, design, and potential as NO donors. J Am Chem Soc 130: 4447–4458.

NIE and LI / Turk J Biol

324

Fang F, Chan JY, Lee AP, Sung SH, Luo XX, Jiang X, Kwong JS, Sanderson JE, Yu CM (2013). Improved coronary artery blood flow following the correction of systolic dyssynchrony with cardiac resynchronization therapy. Int J Cardiol 167: 2167–2171.

Fleissner F, Thum T (2011). Critical role of the nitric oxide/reactive oxygen species balance in endothelial progenitor dysfunction. Antioxid Redox Sign 15: 933–948.

Fuseler JW, Valarmathi MT (2012). Modulation of the migration and differentiation potential of adult bone marrow stromal stem cells by nitric oxide. Biomaterials 33: 1032–1043.

Gao J, Zheng W, Zhang J, Guan D, Yang Z, Kong D, Zhao Q (2013). Enzyme-controllable delivery of nitric oxide from a molecular hydrogel. Chem Commun (Camb) 49: 9173–9175.

Ghaffari A, Miller CC, McMullin B, Ghahary A (2006). Potential application of gaseous nitric oxide as a topical antimicrobial agent. Nitric Oxide 14: 21–29.

Han G, Nguyen LN, Macherla C, Chi YL, Friedman JM, Nosanchuk JD, Martinez LR (2012). Nitric oxide-releasing nanoparticles accelerate wound healing by promoting fibroblast migration and collagen deposition. Am J Pathol 180: 1465–1473.

He N, Xu Y, Du W, Qi X, Liang L, Wang Y, Feng G, Fan Y, Han Z, Kong D et al. (2015). Extracellular matrix can recover the downregulation of adhesion molecules after cell detachment and enhance endothelial cell engraftment. Sci Rep 5: 10902.

Hetrick EM, Shin JH, Paul HS, Schoenfisch MH (2009). Anti-biofilm efficacy of nitric oxide-releasing silica nanoparticles. Biomaterials 30: 2782–2789.

Hiramoto K, Ohkawa T, Kikugawa K (2001). Release of nitric oxide together with carbon-centered radicals from N-nitrosamines by ultraviolet light irradiation. Free Radic Res 35: 803–813.

Hishikawa K, Nakagawa H, Furuta T, Fukuhara K, Tsumoto H, Suzuki T, Miyata N (2009). Photoinduced nitric oxide release from a hindered nitrobenzene derivative by two-photon excitation. J Am Chem Soc 131: 7488–7489.

Hitomi Y, Iwamoto Y, Kodera M (2014). Electronic tuning of nitric oxide release from manganese nitrosyl complexes by visible light irradiation: enhancement of nitric oxide release efficiency by the nitro-substituted quinoline ligand. Dalton T 43: 2161–2167.

Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G (1987). Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. P Natl Acad Sci USA 84: 9265–9269.

Inoue S, Aiba T, Masaoka Y, Shimizu K, Komori Y, Mio M, Takatori S, Kawasaki H, Kurosaki Y (2011). Pharmacodynamic characterization of nitric oxide-mediated vasodilatory activity in isolated perfused rat mesenteric artery bed. Biol Pharm Bull 34: 1487–1492.

Johnson TA, Stasko NA, Matthews JL, Cascio WE, Holmuhamedov EL, Johnson CB, Schoenfisch MH (2010). Reduced ischemia/reperfusion injury via glutathione-initiated nitric oxide-releasing dendrimers. Nitric Oxide 22: 30–36.

Jones M, Ganopolsky JG, Labbe A, Gilardino M, Wahl C, Martoni C, Prakash S (2012). Novel nitric oxide producing probiotic wound healing patch: preparation and in vivo analysis in a New Zealand white rabbit model of ischaemic and infected wounds. Int Wound J 9: 330–343.

Katsumi H, Nishikawa M, Yasui H, Yamashita F, Hashida M (2009). Prevention of ischemia/reperfusion injury by hepatic targeting of nitric oxide in mice. J Control Release 140: 12–17.

Kazakov A, Muller P, Jagoda P, Semenov A, Bohm M, Laufs U (2012). Endothelial nitric oxide synthase of the bone marrow regulates myocardial hypertrophy, fibrosis, and angiogenesis. Cardiovasc Res 93: 397–405.

Kitamura K, Ieda N, Hishikawa K, Suzuki T, Miyata N, Fukuhara K, Nakagawa H (2014). Visible light-induced nitric oxide release from a novel nitrobenzene derivative cross-conjugated with a coumarin fluorophore. Bioorg Med Chem Lett 24: 5660–5662.

Krause BJ, Hanson MA, Casanello P (2011). Role of nitric oxide in placental vascular development and function. Placenta 32: 797–805.

Kuang S, Gillespie MA, Rudnicki MA (2008). Niche regulation of muscle satellite cell self-renewal and differentiation. Cell Stem Cell 2: 22–31.

Kumar D, Branch B, Arora N, Kaushal K, Senthilkumar A, Glawe J, Chidlow J, Teng XJ, Brown M, Lefer D et al. (2007). Nitrite enhances ischemia-induced angiogenesis by nitric oxide dependent pathway. FASEB J 21: A13–A14.

Li Z, Han Z, Wu JC (2009a). Transplantation of human embryonic stem cell-derived endothelial cells for vascular diseases. J Cell Biochem 106: 194–199.

Li Z, Lee A, Huang M, Chun H, Chung J, Chu P, Hoyt G, Yang P, Rosenberg J, Robbins RC et al. (2009b). Imaging survival and function of transplanted cardiac resident stem cells. J Am Coll Cardiol 53: 1229–1240.

Li Z, Suzuki Y, Huang M, Cao F, Xie X, Connolly AJ, Yang PC, Wu JC (2008). Comparison of reporter gene and iron particle labeling for tracking fate of human embryonic stem cells and differentiated endothelial cells in living subjects. Stem Cells 26: 864–873.

Li Z, Wilson KD, Smith B, Kraft DL, Jia F, Huang M, Xie X, Robbins RC, Gambhir SS, Weissman IL et al. (2009c). Functional and transcriptional characterization of human embryonic stem cell-derived endothelial cells for treatment of myocardial infarction. PLoS One 4: e8443.

Liu HA, Balkus KJ (2009). Novel delivery system for the bioregulatory agent nitric oxide. Chem Mater 21: 5032–5041.

Liu K, Ma X, Cao M, Teng C, Li H, Xiao J, Jiang L (2015). Bio-inspired humidity responsive switch for directional water droplet delivery. J Mater Chem A 3: 15540–15545.

Lowe A, Bills J, Verma R, Lavery L, Davis K, Balkus KJ Jr (2015). Electrospun nitric oxide releasing bandage with enhanced wound healing. Acta Biomater 13: 121–130.

Lowe A, Deng W, Smith DW, Balkus KJ (2012). Acrylonitrile-based nitric oxide releasing melt-spun fibers for enhanced wound healing. Macromolecules 45: 5894–5900.

NIE and LI / Turk J Biol

325

Lowe A, Deng W, Smith DW, Balkus KJ (2014). Coated melt-spun acrylonitrile-based suture for delayed release of nitric oxide. Mater Lett 125: 221–223.

Luo JD, Chen AF (2005). Nitric oxide: a newly discovered function on wound healing. Acta Pharmacol Sin 26: 259–264.

Majumder S, Sinha S, Siamwala JH, Muley A, Reddy Seerapu H, Kolluru GK, Veeriah V, Nagarajan S, Sridhara SR, Priya MK et al. (2014). A comparative study of NONOate based NO donors: spermine NONOate is the best suited NO donor for angiogenesis. Nitric Oxide 36: 76–86.

Marcilli RH, de Oliveira MG (2014). Nitric oxide-releasing poly(vinyl alcohol) film for increasing dermal vasodilation. Colloids Surf B Biointerfaces 116: 643–651.

Marletta MA (1993). Nitric oxide synthase structure and mechanism. J Biol Chem 268: 12231–12234.

Marquele-Oliveira F, de Almeida Santana DC, Taveira SF, Vermeulen DM, Moraes de Oliveira AR, da Silva RS, Lopez RFV (2010). Development of nitrosyl ruthenium complex-loaded lipid carriers for topical administration: improvement in skin stability and in nitric oxide release by visible light irradiation. J Pharm Biomed Anal 53: 843–851.

Maruhashi T, Noma K, Iwamoto Y, Iwamoto A, Oda N, Kajikawa M, Matsumoto T, Hidaka T, Kihara Y, Chayama K et al. (2014). Critical role of exogenous nitric oxide in ROCK activity in vascular smooth muscle cells. PLoS One 9: e109017.

Mase JD, Razgoniaev AO, Tschirhart MK, Ostrowski AD (2015). Light-controlled release of nitric oxide from solid polymer composite materials using visible and near infra-red light. Photochem Photobiol Sci 14: 775–785.

Most P, Lerchenmuller C, Rengo G, Mahlmann A, Ritterhoff J, Rohde D, Goodman C, Busch CJ, Laube F, Heissenberg J et al. (2013). S100A1 deficiency impairs postischemic angiogenesis via compromised proangiogenic endothelial cell function and nitric oxide synthase regulation. Circ Res 112: 66–78.

Murrell GAC, Tang GY, Appleyard RC, del Soldato P, Wang MX (2008). Addition of nitric oxide through nitric oxide-paracetamol enhances healing rat Achilles tendon. Clin Orthop Relat R 466: 1618–1624.

Namiki S, Kaneda F, Ikegami M, Arai T, Fujimori K, Asada S, Hama H, Kasuya Y, Goto K (1999). Bis-N-nitroso-caged nitric oxides: photochemistry and biological performance test by rat aorta vasorelaxation. Bioorg Med Chem 7: 1695–1702.

Namkoong S, Chung BH, Ha KS, Lee H, Kwon YG, Kim YM (2008). Microscopic technique for the detection of nitric oxide-dependent angiogenesis in an animal model. Methods Enzymol 441: 393–402.

Napoli C, Ignarro LJ (2003). Nitric oxide-releasing drugs. Annu Rev Pharmacol Toxicol 43: 97–123.

Neidrauer M, Ercan UK, Bhattacharyya A, Samuels J, Sedlak J, Trikha R, Barbee KA, Weingarten MS, Joshi SG (2014). Antimicrobial efficacy and wound-healing property of a topical ointment containing nitric-oxide-loaded zeolites. J Med Microbiol 63: 203–209.

Nguyen KT, Seth AK, Hong SJ, Geringer MR, Xie P, Leung KP, Mustoe TA, Galiano RD (2013). Deficient cytokine expression and neutrophil oxidative burst contribute to impaired cutaneous wound healing in diabetic, biofilm-containing chronic wounds. Wound Repair Regen 21: 833–841.

Oplander C, Muller T, Baschin M, Bozkurt A, Grieb G, Windolf J, Pallua N, Suschek CV (2013). Characterization of novel nitrite-based nitric oxide generating delivery systems for topical dermal application. Nitric Oxide-Biol Ch 28: 24–32.

Oplander C, Romer A, Paunel-Gorgulu A, Fritsch T, van Faassen EE, Murtz M, Bozkurt A, Grieb G, Fuchs P, Pallua N et al. (2012). Dermal application of nitric oxide in vivo: kinetics, biological responses, and therapeutic potential in humans. Clin Pharmacol Ther 91: 1074–1082.

Ostrowski AD, Lin BF, Tirrell MV, Ford PC (2012). Liposome encapsulation of a photochemical NO precursor for controlled nitric oxide release and simultaneous fluorescence imaging. Mol Pharm 9: 2950–2955.

Probst CE, Zrazhevskiy P, Bagalkot V, Gao X (2013). Quantum dots as a platform for nanoparticle drug delivery vehicle design. Adv Drug Deliv Rev 65: 703–718.

Quinn JF, Whittaker MR, Davis TP (2015). Delivering nitric oxide with nanoparticles. J Control Release 205: 190–205.

Rizzo LY, Theek B, Storm G, Kiessling F, Lammers T (2013). Recent progress in nanomedicine: therapeutic, diagnostic and theranostic applications. Curr Opin Biotechnol 24: 1159–1166.

Rochette L, Lorin J, Zeller M, Guilland JC, Lorgis L, Cottin Y, Vergely C (2013). Nitric oxide synthase inhibition and oxidative stress in cardiovascular diseases: possible therapeutic targets? Pharmacol Ther 140: 239–257.

Romanowicz GE, He W, Nielsen M, Frost MC (2013). Novel device for continuous spatial control and temporal delivery of nitric oxide for in vitro cell culture. Redox Biol 1: 332–339.

Rybinski B, Franco-Barraza J, Cukierman E (2014). The wound healing, chronic fibrosis, and cancer progression triad. Physiol Genomics 46: 223–244.

Ryu JH, Lee S, Son S, Kim SH, Leary JF, Choi K, Kwon IC (2014). Theranostic nanoparticles for future personalized medicine. J Control Release 190: 477–484.

Sharma K, Sengupta K, Chakrapani H (2013). Nitroreductase-activated nitric oxide (NO) prodrugs. Bioorg Med Chem Lett 23: 5964–5967.

Singh K, Singh K (2015). Carcinogenesis and diabetic wound healing: evidences of parallelism. Curr Diabetes Rev 11: 32–45.

Sortino S (2012). Photoactivated nanomaterials for biomedical release applications. J Mater Chem 22: 301–318.

Stone T, Berger A, Blumberg S, O’Neill D, Ross F, McMeeking A, Chen W, Pastar I (2012). A multidisciplinary team approach to hydroxyurea-associated chronic wound with squamous cell carcinoma. Int Wound J 9: 324–329.

NIE and LI / Turk J Biol

326

Su W, Zhou M, Zheng Y, Fan Y, Wang L, Han Z, Kong D, Zhao RC, Wu JC, Xiang R et al. (2011). Bioluminescence reporter gene imaging characterize human embryonic stem cell-derived teratoma formation. J Cell Biochem 112: 840–848.

Tan L, Wan A, Li H (2013). Ag2S quantum dots conjugated chitosan nanospheres toward light-triggered nitric oxide release and near-infrared fluorescence imaging. Langmuir 29: 15032–15042.

Tan L, Wan A, Li H (2013). Conjugating S-nitrosothiols with glutathiose stabilized silver sulfide quantum dots for controlled nitric oxide release and near-infrared fluorescence imaging. ACS Appl Mater Interfaces 5: 11163–11171.

Tan L, Wan A, Zhu X, Li H (2014). Visible light-triggered nitric oxide release from near-infrared fluorescent nanospheric vehicles. Analyst 139: 3398–3406.

Velázquez C, Rao PNP, Knaus EE (2005). Novel nonsteroidal antiinflammatory drugs possessing a nitric oxide donor diazen-1-ium-1,2-diolate moiety: design, synthesis, biological evaluation, and nitric oxide release studies. J Med Chem 48: 4061–4067.

Wang JY, Lee CT, Wang JY (2014). Nitric oxide plays a dual role in the oxidative injury of cultured rat microglia but not astroglia. Neuroscience 281C: 164–177.

Wang L, Su W, Du W, Xu Y, Wang L, Kong D, Han Z, Zheng G, Li Z (2015). Gene and microRNA profiling of human induced pluripotent stem cell-derived endothelial cells. Stem Cell Rev 11: 219–227.

Weyerbrock A, Osterberg N, Psarras N, Baumer B, Kogias E, Werres A, Bette S, Saavedra JE, Keefer LK, Papazoglou A (2012). JS-K, a glutathione S-transferase-activated nitric oxide donor with antineoplastic activity in malignant gliomas. Neurosurgery 70: 497–510.

Wu C, McGinity JW (2000). Influence of relative humidity on the mechanical and drug release properties of theophylline pellets coated with an acrylic polymer containing methylparaben as a non-traditional plasticizer. Eur J Pharm Biopharm 50: 277–284.

Yang K, Feng LZ, Shi XZ, Liu Z (2013). Nano-graphene in biomedicine: theranostic applications. Chem Soc Rev 42: 530–547.

Yao X, Liu Y, Gao J, Yang L, Mao D, Stefanitsch C, Li Y, Zhang J, Ou L, Kong D et al. (2015). Nitric oxide releasing hydrogel enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction. Biomaterials 60: 130–140.

Yepuri NR, Barraud N, Mohammadi NS, Kardak BG, Kjelleberg S, Rice SA, Kelso MJ (2013). Synthesis of cephalosporin-3’-diazeniumdiolates: biofilm dispersing NO-donor prodrugs activated by beta-lactamase. Chem Commun (Camb) 49: 4791–4793.

Zhang XF, Mansouri S, Mbeh DA, Yahia L, Sacher E, Veres T (2012). Nitric oxide delivery by core/shell superparamagnetic nanoparticle vehicles with enhanced biocompatibility. Langmuir 28: 12879–12885.

Zhao Q, Li Z (2015). Angiogenesis. BioMed Res Int 2015: 135861.

Zhao Q, Zhang J, Song L, Ji Q, Yao Y, Cui Y, Shen J, Wang PG, Kong D (2013). Polysaccharide-based biomaterials with on-demand nitric oxide releasing property regulated by enzyme catalysis. Biomaterials 34: 8450–8458.