Chemical structures of cellulosic and synthetic polymeric membranes for blood purification.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
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\\n"}]',published:!0,mainMedia:{caption:"IntechOpen Maintains",originalUrl:"/media/original/113"}},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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When functions of the living kidney decrease down to under survival level, patients are required to be treated with a system that supports kidney functions. There are several such treatment modalities available, including peritoneal dialysis (PD), hemodialysis (HD), hemofiltration (HF), hemodiafiltration (HDF), hemoadsorption (HA), and their advanced derivatives, among which the most popular treatment system is HD. The artificial kidney device used in HD is called “hemodialyzer” or more simply “dialyzer” that includes membrane to separate the waste products and excess water from blood.
\nArtificial kidney is also expected to correct pH that is usually acidic before treatment by balancing electrolytes in addition to removing waste products and excess water. All these functions are dependent upon the permeability of the membrane used in a dialyzer and since the quality of treatment is strongly dependent on the performance of the dialyzer, many materials have been proposed as a candidate of the membrane. We have currently several commercial materials available, including natural polymers and synthetic polymeric ones.
\nIn this chapter, dialysis membrane and its materials are extensively discussed from the physicochemical points of view, including microscopic views taken by scanning electron microscope (SEM), mathematical expressions of membrane transport, fundamental
Dialysis is a phenomenon at which two different fluids (usually liquids) are separating flowing on either side of the membrane (usually counter-currently) and the solute of interest in higher concentration transports across the membrane due to concentration gradient in accordance with the Fick’s 1-st law of diffusion, i.e.,
\nwhere
where
Diffusion across a piece of membrane assuming no existence of boundary film adjacent to either side of the membrane.
Application of dialysis to blood purification, hemodialysis (HD), was first performed for canines reported by Abel
Cuprophan® is a registered name of the membrane made of cuprammonium rayon made from cellulose dissolved in cuprammonium solution, produced by Enka Co. in West Germany, later Membrana in Polypore Co., Germany. Another cuprammonium rayon membrane with nearly the same chemical and physical structures was developed by Asahi-Kasei Co. (Tokyo, Japan) termed Bemberg®, followed by Terumo (Tokyo, Japan). These membranes were also called regenerated cellulosic (RC) membrane since they were cast from cellulose or cotton fibers. Chemical modifications were made for RC membranes mostly because of improving their biocompatibility by replacing their hydroxyl group(s) with acetate group(s). They are called cellulose acetate (CA), cellulose diacetate (CDA), and cellulose triacetate (CTA) in accordance with the number of introduction of acetate groups to the cellulose backbone. Although RC membranes are no longer commercially available, CA, CDA, and CTA membranes still have fairly good market share since they have much higher solute and hydraulic permeabilities as well as better biocompatibility than original RC membranes.
\nThe first synthetic polymeric membrane was developed in 1969 by Rhône-Poulenc (France) and was named AN-69®, since the main material of the membrane was acrylonitrile (AN). The brand name of the dialyzer assembled with a flat sheet AN-69® membrane was RP-6® and it was also the first dialyzer sterilized by the gamma-ray irradiation. Although the production company of AN-69® membrane has been changed over time from Rhône-Poulenc to Hospal, Gambro, and Baxter, dialyzers with AN-69® membrane are still available worldwide, especially in the field of acute kidney injury (AKI) therapy since it has strong adsorption characteristic to specific substances such as inflammatory cytokines.
\nThe first dialyzer with a cellulosic hollow fiber membrane was developed by chemical engineers, Stuart and Lipps in 1967 [3] in Massachusetts Institute of Technology (Boston, MA, U.S.A.), and the commercial product was available in 1972 from Cordis-Dow Co. (Miami, FL, U.S.A.). The basic structure of the hollow-fiber dialyzer is the same as the one of multi-tube heat exchanger that is compact and has large surface area. Because of these advantages, dialyzers with hollow fiber membrane have been become widely used. The first dialyzer with a synthetic polymeric hollow fiber membrane sterilized by gamma-ray was introduced by Toray Co. (Tokyo, Japan), in which polymethylmethacrylate (PMMA) was used as a main material of the membrane [4].
\nIn order to improve solute and hydraulic permeabilities as well as biocompatibilities, many synthetic polymeric membranes have been introduced to the market since early 1980’s, and currently these membranes are the main stream. Among them, polysulfone (PSf) and the like (including polyethersulfone (PES), polyarylethersulfone (PAES), etc.) have the highest market share over the world. Since these membranes are made from petroleum, they are hydrophobic in nature. Then most of these membranes include so-called hydrophilic agent that also plays a role of pore-forming agent when cast. The role of the hydrophilic agent is discussed later from the chemical (section 3), mass transport (section 4), and biological (section 5) points of view.
\nChemical structure of the dialysis membrane usually refers to the chemical structural formula of the main material(s) of the dialysis membrane. Most chemical structural formulae of the main material of the membrane are tabulated in Table 1, including both natural and synthetic polymers. Among them AN-69®, ethylenevinylalcohol (EVAL) co-polymer, polyester polymer alloy (PEPA, Nikkiso Co., Tokyo, Japan, Figure 2) include two main materials. Actually PMMA is also a stereo complex co-polymer of two kinds of PMMA, isotactic and syndiotactic. Isotactic PMMA has acetate groups on only one side of the main chain, resulting a curled structure, whereas syndiotactic PMMA has acetate groups alternately on either side of the main chain, resulting a fairly straight structure. Combining these two polymers, membranes with low to high hydraulic permeability has been brought to realization [4].
\nChemical structures of polyester polymer alloy (PEPA) composed of PES and PAR with polyvinylpyrroridone (PVP).
Chemical structures of cellulosic and synthetic polymeric membranes for blood purification.
In general, cellulosic membranes are hydrophilic in nature, including original RC and its derivatives such as CA, CDA, and CTA in which hydroxyl group(s) are replaced by acetate group(s). On the contrary, since synthetic polymeric membranes are originated from petroleum, generally speaking they are hydrophobic in nature. Blood coagulation usually occurs soon after blood interacts with hydrophobic materials. Most synthetic polymeric membranes, therefore, include so-called hydrophilic agent such as polyvinylpyrrolidone (PVP) to make membrane hydrophilic. Figure 2 includes the chemical structure of PVP together with two other polymers (polyarrylate and polyethersulfone). PEPA is composed of these two polymers with or without PVP, the former shows little hydrophobicity, while the latter has strong adsorptive characteristic to various proteins due to its hydrophobicity (see section 4).
\nSince PVP is water-soluble, excess amount of PVP may be rinsed out from the membrane after cast that forms pores for solute and water transport. Therefore PVP is also known as a pore-forming agent. Namely, it should be understood that PVP residues in or on the membrane after rinse behave as a hydrophilic agent. Both an average and a distribution of molecular weight of PVP are important as well as the amount of PVP used in the membrane. Moreover, PVP may be cross-linked together and to the main material of the membrane by irradiating gamma-ray in the final sterilization process. With this procedure, PVP should be tightly attached together and/or on the membrane that does not allow PVP to behave as a “cushion” (cushion effect) to the blood corpuscles [5].
\nAcrylic acid is specifically chosen for polyacrylonitrile (PAN, Asahi Kasei, different from AN-69®) as a hydrophilic agent, whereas no hydrophilic agent is used in PMMA, EVAL and the original PEPA in which micro-layer separation technology plays a significant role in casting procedure.
\nPhysical structures can be demonstrated in the following two ways, i.e., microscopic view analysis and a theoretical analysis based on mathematical models. Microscopic views are usually taken by a scanning electron microscope (SEM). Recently the microscope technology has been advancing drastically and a field-emission SEM (FE-SEM) that has much higher resolutions can be utilized widely.
\nA cross-sectional view of EVAL hollow fiber membrane (Asahi-Kasei, Tokyo, Japan) taken by FE-SEM.
\n Figure 3 is a FE-SEM of intersection of EVAL membrane (Asahi-Kasei). It is entirely a dense membrane and the entire thickness contributes to the transport resistance for solutes and water. Membranes of this kind are usually called “homogeneous.” Besides EVAL, PMMA, and AN-69®, most cellulosic membranes are homogeneous. Figure 4 shows a cross-sectional view of PSf membrane (Toray). One should realize that a dense thin layer exists on the inner surface of the membrane, called “skin layer” from which the density is gradually decreasing in the radial direction. Since most part excluding the skin layer is known to have little resistance for solute and water transport, it is called the “support layer” (Figure 5). The support layer, however, has an important role for the membrane to have enough mechanical strength with little resistance for transport. Membranes of this kind are called “asymmetry.” Most synthetic polymeric membranes (except for PMMA, EVAL, and AN-69®) are asymmetry. In general, although the physical thickness of synthetic polymeric membranes is thicker (approximately 35 μm) than that of cellulosic membranes (approximately 15 μm), the thickness that contributes to the separation (
A cross-sectional view of PSf hollow fiber membrane (Toray, Tokyo, Japan) taken by FE-SEM.
Cross-sectional views of dialysis membranes.
The pore theory is often used to analyze and to design physical structures of the membrane. The original pore theory was introduced by Pappenheimer
Pore theory (pore diffusion model). Assuming pores whose radius is uniformly
where
From Eqs.(3) and (4), it is clear that
\n \n
Portions of two modeled membranes with the same surface porosity.
Then one would realize that membranes (A) and (B) have the same surface porosities, although the situations are quite different in terms of the pore diameter.
\nExample)
\nCompare the two membranes (A) and (B) that have the same surface porosity (Figure 7), tortuosity and the thickness in terms of
\nhydraulic permeability
solute permeability
under the following two conditions
\n
\n
Solution) As stated above,
Recalling Eq. (4) to get,
\n \n
Therefore, the membrane (B) has four times higher hydraulic permeability than the membrane (A).
\nSince
\n
in both membranes (A) and (B). Therefore Eq.(3) may be simplified as follows,
\nConsequently, there is no difference between membranes (A) and (B) in terms of transport of small solutes.
\nRecalling Eq.(5),
Then recalling Eqs.(7) and (9) with
\n
\n
\n
\n
Then from Eq.(3),
\n\n \n
Finally one would conclude that the membrane (B) has almost two times higher solute permeability than the membrane (A) for those solutes whose
Chemical characteristic determines the hydrophilicity and hydrophobicity of the material, whereas physical structure determines the pore sizes as well as the thickness that contributes to the transport resistance. Therefore, both chemical and physical features are important for designing dialysis membrane.
\nIn this section, we discuss the performances under
Six filters (dialyzers), one with PSf (PS-1.6UW, Fresenius-Kawasumi Co., Tokyo, Japan) and other five with PEPA (Nikkiso Co., Tokyo, Japan) were investigated (Table 2). Since both PSf and PEPA are hydrophobic in nature, these membranes include PVP for anti-thrombosis purpose, except for one dialyzer that includes PEPA membrane with no additives (FLX). Amount of PVP used in the membrane is semi-quantitatively shown as (+++), (++), (+), and (-), respectively for “most”, “much”, “small” and “none”.
\n\n | \n \n | \n \n | \n \n | \n \n | \n \n | \n \n | \n \n | \n
1 | \nPS-1.6UW | \nPS | \n1.6 | \nPSf | \nPVP (+++) | \n(Not available) | \nFresenius Medical Care, Badhonburg, Germany | \n
2 | \nFLX-15GW | \nFLX | \n1.5 | \nPEPA | \nPVP (-) | \nstandard | \nNikkiso Co., Tokyo, Japan | \n
3 | \nFDX-15GW | \nFDX | \n1.5 | \nPEPA | \nPVP (+) | \nstandard | \nNikkiso Co., Tokyo, Japan | \n
4 | \nFDY-15GW | \nFDY | \n1.5 | \nPEPA | \nPVP (+) | \nlarger | \nNikkiso Co., Tokyo, Japan | \n
5 | \nFDX-150GW | \nnew FDX | \n1.5 | \nPEPA | \nPVP (++) | \nstandard | \nNikkiso Co., Tokyo, Japan | \n
6 | \nFDY-150GW | \nnew FDY | \n1.5 | \nPEPA | \nPVP (++) | \nlarger | \nNikkiso Co., Tokyo, Japan | \n
Technical specification of investigated ultrafilters
The time courses of the sieving coefficient (
Time courses of the sieving coefficient for albumin under various concentrations of albumin in PS-1.6UW (PSf membrane)
The time courses of
Time courses of the sieving coefficient for albumin under a fixed albumin concentration (3.64 mg/mL) in three PEPA membrane dialyzers Curves are different from the ones found with PSf membrane.
The time courses of
Time courses of the sieving coefficient for albumin under a fixed albumin concentration (3.64 mg/mL) in two new PEPA membrane dialyzers Curves are similar to the ones found with PSf membrane.
Since the albumin concentrations of the test solutions were lower by the factor of 1/30-1/10 to the standard albumin concentration in human blood (3.6 – 4.0 g/dL),
According to the Japanese reimbursement system, all the commercial dialyzers are classified into five categories in accordance with the clearances for β2-microglobulin (β2-MG, MW 11800) under
Classification of dialyzers in Japanese reimbursement system
1. Flow conditions:
2.
3.
Although 99 uremic toxins are compiled by Vanholder [13], clinicians and researchers have different opinions on which solutes to be removed or up to how much albumin may be leaked out. Figure 11 shows the relationship between the reduction rate of β2-MG and albumin loss taken with various dialyzers in different modalities. Only a limited increase in β2-MG reduction was found with the increase of albumin removal. Therefore β2-MG removal may not be directly related to convection transport when super-high flux dialyzers are used. In other words, super high-flux dialyzers are the ones in which β2-MG removal does not correlate with the amount of albumin loss or the convection transport.
\nRelationship between the reduction rate of β2-microglobulin (MW: 11,800) and albumin loss.
\n Figure 12 shows the same relationship between the reduction rate of α1-microglobulin (α1-MG, MW 33,000) and albumin loss. Up to albumin loss of 3 g/session, almost linear relationship was observed, meaning that it may not be possible to remove α1-MG without removing albumin, although the molecular weight of albumin is twice as large as that of α1-MG. There is no such article that reports α1-MG is toxic; moreover, α1-MG is not even included in Vanholder’s list [13]. We, however, experienced fairly good number of patients who have become better with albumin loss of 3 g or more for bone pain, shoulder pain, and improvement of fingertip power, and 5 g or more for finger numbness, restless legs syndrome. Therefore α1-MG may be a possible surrogate marker of HDF treatment for those who have symptoms with normal HD therapy. Relief of clinical symptoms with various treatment modalities is summarized in Figure 13.
\nRelationship between the reduction rate of α1-microglobulin (MW: 33,000) and albumin loss.
Relief of clinical symptoms by employing various protein-losing treatment modes.
On-line HDF is mostly performed in post-dilution mode with high
Many randomized control studies have been done in order to verify superiority or better outcomes of on-line HDF [15-[19]; however, we have not yet come into a conclusion that states on-line HDF is better than other treatment modalities. These studies showed that on-line HDF was at least better than low-flux HD; however, the difference between on-line HDF and high-flux HD was ambiguous [18, 19], in terms of survival rate within a study period of three years or so. Post–hoc analyses and sub-analyses of those studies showed superiority of on-line HDF with large amount of fluid exchange (at least > 15 L) to other treatment modalities in terms of dialysis-induced hypotension, reaction to ESR medications, as well as survival rate. Among them, the ESHOL study [20] greatly encouraged patients on dialysis as well as medical staffs in which on-line HDF showed better clinical outcomes in all the end points than high-flux HD. Many debates, however, still continues also elsewhere including in Japan where the number of patients on on-line HDF is rapidly growing and exceeded 10 % of the total patients [21].
\nBiological consideration of the dialysis membrane is often referred to biocompatibility. Since dialyzers are repeatedly used four hours a session, three times a week, even a small event that repeatedly would occur each time may cause undesired side effects such as chronic inflammation.
\nUp until 1970s, RC membrane dominated over the market, and it was gradually replaced by synthetic polymeric membranes. Transient leukopenia that is an abrupt decease of leukocytes occurs at 15 to 30 minutes after starting the treatment has been one of the best known bio-incompatible events [22]. Reprocessing dialyzers was common in 1970’s and since bio-incompatible events were often found when a dialyzer was used for the first time, this was called the “first use syndrome” [23].
\nCraddock
It is well known that the Glomerular basement membrane (GBM) in human kidney is negatively charged. Although AN-69® is also a negatively charged membrane, one must pay much attention for the use of this membrane because it may cause anaphylaxy shock soon after starting the treatment [25]. Strong negative charge (-70 mV) would activate Hageman (XII) factor to XIIa that eventually produces bradykinin from kininogen as a substrate. Under normal situation bradykinin may be deactivated by kininase II; however, if the patient takes angiotensin-converting enzyme (ACE) inhibitor, it deactivates kininase II. This would induce the cascade reaction with bradykinin, including NO generation, increased vascular permeability, expansion of blood vessels, suppressing blood pressure, and ending up with shock during the treatment. This is often called “negative charge syndrome” (NCS, Figure 14). Although all dialysis membranes are negatively charged, it is usually a contraindication to prescribe ACE inhibitor to a patient under the use of AN69®.
\nMechanisms of negative charge syndrome (NCS).
Hemophan® was developed by introducing a positively charged substance, diethylaminoethyl (DEAE), to RC membrane in order to improve its surface character (Membrana, Germany). Although only a limited amount of DEAE was introduced relative to entire amount of cellulose, complement activation was greatly suppressed. Hemophan®, however, adsorbed heparin, which induced blood coagulation. Because of this fact, the production of this membrane was ceased. Another trial was made by coating the membrane surface with vitamin E in order to make the RC membrane antioxydative (Terumo, Tokyo, Japan). Later, this technique was applied to PSf membrane and the commercial model is still available (Asahi Kasei Medical Co., Tokyo, Japan).
\nPSf and the ones whose chemical structures are similar to PSf have the highest market share among all dialysis membranes. They usually include polyvinylpyrrolidone (PVP) as a hydrophilic agent since they are hydrophobic in nature. PVP was once used as a supplement of plasma in medicine. Anaphylaxy shock, however, was reported, the cause of which was strongly doubted to be the PVP included in the membrane. Then we performed the following clinical investigation by using dialyzers with PSf and the ones with PEPA membrane with different amount of PVP [11].
\nTime course of C3a change during four hr treatment. The same PSf dialyzers with PVP(+++) were used in the 1-st and last (7-th) weeks. The same FDY dialyzers with PVP(+) were used from the 2nd to the 6th weeks.
The time course of C3a concentration profile in clinical study is shown in Figure 15. PSf with PVP(+++) showed three times higher concentration 15 minutes after the start of treatment. The C3a elevation was slightly lower at the first use of PEPA with PVP(+) and the peak concentrations were approximately halved or even less from the second to the fifth week. The peak concentration, however, returned back to three folds in the first use of PSf after five-week use of PEPA with PVP(+).
\nAccording to another clinical data shown in Figure 16, PSf with PVP(+++) showed highest C3a elevation, followed by PEPA with PVP(++), PVP(+), and PVP(-). The degree of C3a elevation was a function of amount of PVP included in the membrane regardless of the main material of the membrane.
\nTime course of C3a change during four hr treatment in 1 patient. Symbols are arranged in the chronological order from the top to the bottom.
From these results, we learned that PVP may not be the best choice as a hydrophilic agent in terms of blood compatibility.
\nWith above mentioned technique, we will be able to expect an even better dialysis membrane to come into the market. Several futuristic functions desired for dialysis membrane is also introduced, expecting a new era to come. Followings are the problems to be solved in the future perspectives of dialysis membrane.
\nSince on-line HDF has been gaining popularity in European countries as well as in Japan, HDF with much larger amount of fluid exchange has to be more easily performed for the further success of this modality. Standard on-line HDF in European countries is performed in post-dilution system with
Comparison of post-dilution and pre-dilution on-line HDF with typical European and Japanese flow rates, respectively.
According to the Italian study [17], on-line HDF/HF is a useful tool for treating patients with dialysis induced hypotension. Then diafilters with higher hydraulic permeability with little albumin loss that do not aim to achieve higher solute removal may be useful for those patients. Not to mention, design specifications of dialyzer/diafilter is as important as the membrane permeability in terms of solute removal under given therapeutic conditions.
\nMany classic problems with biocompatibility in the past such as transient leukopenia, complement activation, negative charge syndrome, etc., have already been dissolved by modifying physical and chemical structures of the dialysis membrane. Most currently available synthetic polymeric membranes, however, employ PVP as a hydrophilic agent as well as a pore-forming agent. Study shows that many symptoms including abrupt decrease of blood pressure or shock right after starting treatments could be induced most probably due to PVP included in the membrane, and it is sometimes called “PVP intolerance”. Novel hydrophilic agents may be studied for the purpose of replacing PVP. Alternately, novel casting technique in which no hydrophilic agent is necessary has to be studied, knowing that PMMA, EVAL, and PEPA are cast with no additives although they are also originated from petroleum.
\nSurface modification with the third substances is another way to obtain membranes with preferred permeability as well as biocompatibility. For example, PSf membrane coated with vitamin E showed a great success for reducing reactive oxygen species (ROS) as well as free radicals that also showed preferable clinical results (Terumo, Asahi-Kasei). Toray introduced a novel technique with NV polymer to their PSf membrane to reduce adsorption of cells as well as protein molecules on the membrane. Although both two membranes work well clinically, they still utilize PVP in the same amount as previously included before. Then it should be noted since surface modification is closely related to solute transport as well as biocompatibility, biomimicry situations under dialysis must be further taken into consideration.
\nSince hemodialysis experiments with canines were first reported, many membranes, either natural or synthetic polymeric ones, have been developed and the latter have been the main stream due to higher solute and hydraulic permeabilities as well as better biocompatibility. The mass transport mechanism across the membrane can be expressed by the Fick’s 1-st law of diffusion; however, not only the membrane permeability but also the design specifications are important for assembling dialyzers with better performances.
\nThe chemical structure of the dialysis membrane determines the hydrophilicity and hydrophobicity of the membrane. Since all synthetic polymeric membranes are made from petroleum, they are hydrophobic in nature. Most of these membranes include a hydrophilic agent such as PVP for anti-thrombosis purpose. According to the in vitro experiments and clinical observations, it was proved that PVP was closely related to the sieving coefficient for albumin and had big influence on the complement activation. Then we must pay much attention on additives in addition to the main material(s) of the membrane.
\nPhysical structure of the dialysis membrane can be discussed in two ways, i.e., direct observations by taking microscopic views (SEM) and the theoretical analysis by using a mathematical model. There are two kind of dialysis membranes, “homogeneous” and “asymmetry”, among which the latter is gaining popularity because of the much smaller thickness that contributes to the resistance of solute and water transport. The pore theory is a useful tool for analyzing mass and water transport across the membrane and for designing a physical structure of the membrane.
\nSince the number of on-line hemodiafiltration (HDF) is growing these days not only from the solute removal point of view but also from the improvement of dialysis-induced hypotension during the treatment, membranes specifically designed for performing HDF has to be more extensively studied both clinically and fundamentally. Importance of biocompatibility of the membrane should be more carefully taken into account for selecting a device, considering membrane characteristic such as adsorption, especially in the field of acute kidney injury (AKI).
\nAngiogenesis is an important biological process which involves the development of new capillary network from the pre-existing vasculature [1, 2]. The process of angiogenesis is indispensable in supplying oxygen and nutrients to cells under hypoxia, and it has been implicated in different physiological processes such as wound healing, embryogenesis etc. It has also been reported to play key role in many pathologies including diabetic retinopathy and cancer [3]. Angiogenesis is a multi-step process, which commences when the primary, pro angiogenic cytokine, VEGF, is secreted by the cells experiencing hypoxia. Thereafter the interaction of VEGF with its receptor (VEGFR2) on the nearby endothelial cells (EC), leads to EC activation, proliferation, migration, extra cellular matrix (ECM) remodeling, tube formation followed by loop formation leading finally to neo vessel formation and vascular stabilization [4, 5].
The process of angiogenesis is regulated by multiple factors, which may be pro- or anti-angiogenic in nature. The endogenous pro angiogenic factors include growth factors like VEGF, PDGF, FGF, EGF, angiopoietin-1, interleukin-8, placental growth factor, angiogenin etc. The anti- angiogenic factors include endostatin, angiostatin, prolactin, fibronectin, vasostatin, interleukin-12, platelet factor 4 etc. [6, 7]. An equilibrium exists between the pro- and anti-angiogenic factors under physiological conditions, and any disturbance in that equilibrium would result in pathological manifestations [3]. Targeting angiogenesis therefore has drawn huge attention with respect to the therapeutics of pathologies were excessive or insufficient angiogenesis prevails [7]. One of the major approaches in angiogenesis targeted therapy involves targeting VEGF signaling pathway. Humanized monoclonal antibody targeting VEGFA, namely, Bevacizumab, with the approval of US Food and Drug Administration (FDA), has been employed in a combination therapy for the treatment of metastatic colorectal cancer [8]. In addition, an aptamer which inhibits VEGF 165, namely, Pegaptanib has been approved by FDA to treat Age related macular degeneration [9]. In spite of all such interventions, targeting angiogenesis demands much more explorations due to a variety of unresolved issues such as development of resistance to antiangiogenic therapy, lack of adequate treatment for ischaemic disorders etc. [10].
In an urge to overcome the limitations of conventional angiogenic therapy, researchers globally have focused on developing ‘nanomedicines’ for the treatment and diagnosis of various diseases associated with aberrant angiogenesis [11]. The field of nanomedicine involves the use of nanomaterials for biological and medicinal applications by virtue of their ability to interact with nucleic acids, proteins and membrane receptors effortlessly [10]. In this chapter, we have therefore focused on various research achievements pertaining to candidate nanomaterials that can be developed as potential drugs for angiogenic therapy.
The class of substances having at least one dimension less than 100 nano meters are called nanoscale materials and the field of science that deals with the synthesis, study of structure, physical and chemical properties and applications of various types of nanoscale materials is referred as Nanotechnology [12]. Nanomaterials usually occur as zero, one, two and three-dimensional structures. Generally, the nanoparticles are comprised of three layers called the surface layer, the shell layer and the core. The core is the central portion of the materials surrounded by the shell and surface layer. The shell layer is chemically different from the core and the outer layer. The surface layer permits surface modification with a variety of moieties like polymers, metal ions, and surfactants [13]. The physical and chemical properties of bulk materials are independent of their size, however, when converted into nano scale materials their optical, physical, mechanical and chemical properties vary according to their size [14]. Such properties include solubility, color, toxicity etc. The major reason for these improved properties of nanomaterials are due to their high surface mass ratio as compared with the bulk [15]. Due to their unique size, shape, structure and solubility they have found application in the biomedical, optical, sensor, electric and energy harvesting fields. Many nanomaterials are already being explored for their use in biomedical imaging [16], bio/chemical sensing [17], targeted gene and drug delivery [18]. We here focus on candidate nanomaterials which are potential nanomedicines in the field of therapeutic angiogenesis.
Based on the origin, size, morphology and chemical composition, nanomaterials are divided into various categories. In the present chapter we are focusing on some of the important classes that have found applications in biological field.
Metal nanoparticles are those particles which may be the pure metal or metal compounds like metal oxide, hydroxides, sulphides etc., exhibit size in the submicron scale. A variety of metal nanoparticles has been synthesized with varied structural morphology, size and compositions [19]. These metal nanoparticles can be synthesized from various metal precursors and can be functionalized with several groups [20]. The metal nanoparticles permit surface modification with various chemical functional groups and further allow them to be conjugated with polymers, ligands, antibodies etc. The improved surface mass ratio, shape, morphology and functionality, quantum confinement and plasmon excitation make them suitable for the applications in the field of energy, catalysis, electronics, and medicine [21]. However, they show some demerits such as tendency to get agglomerate and chances of formation of impurities due to their high reactivity. Many of the nanomaterials except gold, silver, and platinum exhibits high cyto-toxicity.
Among the various carbonaceous nanomaterials, the zero-dimensional carbon-based quantum dots (CQDs and GQDs), one-dimensional carbon nanotubes (CNTs) and two-dimensional graphene (GR) are currently the most popular nanocarbon representatives in biological applications [22]. Carbon-based QDs are the recent extension in the nano carbon family with fascinating properties like biocompatibility, resistance to photobleaching and attractive photoluminescence. These outstanding properties make them smart candidates for bioimaging, sensing, drug delivery and cancer therapy [23, 24]. CNTs have a unique 1D nanostructure, with sp2 hybridized carbon atoms rolled up to design a cylindrical shape. They exist as both single-walled CNTs and multi-walled CNTs depending on the number rolled-up graphene sheets. Due to their exceptional structural, mechanical, and electrical diversities, they deliver remarkable flexibility, strength, and electrical properties suitable for various biological applications like medical diagnostics, sensing and treatment of diseases. Graphene represents the 2D nano allotrope of carbon illustrating a planar graphitic structure with sp2 hybridized carbon network. Its surpassingly large surface area, easy functionalization and chemical purity makes it a potential candidate for drug delivery. Moreover, it is also widely explored for
Polymeric nanoparticles are constructed with the aid of natural or synthetic polymers. As compared to other nanoparticles, they offer advantages like non-toxicity and biocompatibility suited for specific biological applications. Although they are used for biosensing and bioimaging, the major purpose of polymeric nanoparticles lies in the field of drug delivery [25]. Biomolecules or drugs are encapsulated into polymeric nanoparticles to obtain a gradual and continuous release of the drugs at the specifically targeted sites.
Nanoscale ceramics, which include various ceramic nanoparticles of zirconia, hydroxyapatite, alumina and titanium oxide have also found potential biological applications. Some of the distinct features like high load capacity, stability and effortless incorporation to hydrophilic and hydrophobic systems enhance their efficiency in the field of biomedicine, however, work on scaling down its cytotoxicity remains to be addressed before its full-fledged use in the biological system [26].
Semiconductor nanoparticles, particularly QDs have been heavily explored for a wide variety of biological applications like biosensing, molecular imaging, live-cell labelling and drug delivery. They possess unique optical properties like a long fluorescence lifetime and low photobleaching when correlated with conventional organic dyes and fluorescent polymers [27]. Although, the toxicity of the traditional semiconductor QDs is a typical concern that has to be addressed for
Lipid-based nanoparticles, consisting of liposomes, nanostructured lipid carriers and solid lipid nanoparticles have gained tremendous attention in the field of cancer treatment and drug delivery. These nanoparticles exhibit very low toxicity, can act as a carrier for both hydrophilic and hydrophobic molecules and ensures controlled release of drugs. Due to its versatility and biocompatibility, liposomes are the extensively utilized lipid-based nanoparticles [28].
Abnormal or excessive angiogenesis has been reported to be involved in the progression of a wide variety of diseases affecting different organs. For example, aberrant angiogenesis has been implicated to promote diseases like tumor, auto immune disorders and infectious diseases caused by the pathogens inducing angiogenesis and such diseases have been reported to affect multiple organ systems [29]. Further, it has also been reported to be involved in the advancement of skin tissue associated diseases like psoriasis, allergic dermatitis, blistering disease, scar keloids etc. In addition, it has been reported to be the major cause for diabetic retinopathy and choroidal neovascularization associated with wet type AMD, which affect the eyes [29]. Abnormal angiogenesis has also been reported to be involved in the progression of blood vessel associated disorders like atherosclerosis, transplant arteriopathy etc. [30]. The involvement of angiogenesis has also been reported in the progression of primary pulmonary hypertension, asthma and nasal polyps [29]. In addition, it has also been reported in the progression of diseases that affect the reproductive system, which include ovarian hyper stimulation, endometriosis etc. [31]. Aberrant angiogenesis has also been the leading cause for the progression of diseases like osteomyelitis which is characterized by impaired osteogenesis [29]. It has also been reported to promote nerve system associated diseases like diabetic neuropathy and amyotrophic lateral sclerosis, which are characterized by nerve tissue degeneration [32]. The process of angiogenesis has also been reported to promote physiological processes like wound healing and discrepancy associated with that could lead to complications like development of chronic wounds [33]. Different candidate disorders associated with aberrant angiogenesis and the candidate nanomaterials that can be developed as potential drugs for the treatment of such disorders have been detailed below.
The essentiality of angiogenesis in the progression of tumor growth was a breakthrough finding by Judah Folkman way back in 1971, which opened up an era of investigations, concerned with targeting angiogenesis for cancer therapeutics. It has been established that a tumor cannot grow beyond 2 mm in diameter without a steady supply of oxygen and nutrients by means of angiogenesis [34, 35, 36]. Therefore, preventing the neovascularisation has been suggested as one of the key strategies for cancer therapeutics. Angiogenesis in a tumor micro environment, unlike that under physiological conditions, is characterized by the formation of immature, leaky blood vessels, resulting in a continual state of inflammation. This happens mainly due to the increased expression of a variety of pro angiogenic factors including VEGF, angiopoietin, integrins etc. and such factors are being targeted for anti-angiogenic therapy. Anti-angiogenic agents targeting VEGF, such as Bevacizumab has been approved by FDA, however, release of other pro angiogenic factors over ruled the efficiency of such mono-therapies [37, 38, 39, 40]. Therefore, combination therapies using multiple anti-angiogenic agents were more appreciated to quick fix resistance to angiogenic monotherapy.
Nanoparticles (NPs) could be employed as a vehicle to deliver multiple drugs, targeting different molecules and pathways associated with tumor angiogenesis [37, 41]. The therapeutic drugs are generally loaded on to the NPs either by chemical conjugation or by encapsulation [38]. The NP-based drug delivery can either be passive or active in mode. The presence of leaky blood vessels in the vicinity of tumors facilitates the passive extravasation of NPs with size less than 200 nm into the tumor site by the Enhanced Permeability and Retention effect (EPR) and such NPs are later on cleared by the liver [39, 42]. In addition, limited lymphatic drainage facilitates the retention of NPs at the site of tumors which in turn promotes sustained drug delivery [39]. It has been reported that NP conjugated Doxorubicin [43, 44] and small molecule inhibitors of angiogenesis [45] could accumulate in the tumor micro environment by EPR effect, which lead to the stoppage of tumor angiogenesis and tumor growth [38]. Further, Caplostatin (TNP-470), an angiogenic inhibitor, has been reported to get selectively piled up in the blood vessels associated with tumors by EPR effect which in turn blocked tumor associated vascular hyperpermeability [46, 47]. The Active targeting of tumor vasculature by NPs is achieved by means of ligands presented on NP surfaces. The ligands would selectively bind to receptors which are over expressed on tumor cells as well as on tumor associated ECs, such receptors include VEGFRs, αvβ3 integrins etc. [38, 48].
NP mediated targeting of different miRNAs have also been tested for their therapeutic efficacy [49]. For instance, treatment with NP containing anti-miR-21 (CTX-SNALP-anti miR-21) has been reported to silence miR-21 in patients with glioblastoma resulting in an increase in the levels of its target gene RhoB both at mRNA and protein levels. Further, NP mediated administration of anti-miR-21 has been reported to inhibit tumor proliferation, induce apoptosis and promote survival rate in the animal model [49]. Exosomes are endogenous lipid-based NPs which are involved in the transfer of biomolecules like RNA and proteins between cells. It has been reported that miR-23a encapsulated exosomes could effectively induce angiogenesis in CAM model as well as in
Different metal NPs like gold and silver NPs have been reported to be effective for anti-angiogenic therapy. It has been reported that gold NPs (AuNPs) are capable of binding to the heparin binding domains of various growth factors like VEGF165 and bFGF leading to the conformational changes associated with the impaired functioning of such growth factors. AuNP mediated inhibition of VEGF was found to be negatively regulating the phosphorylation of VEGFR2. The inhibitory effect of AuNPs on Heparin binding growth factors (HB-GFs) was found to be greatly depended on the size of AuNPs, further, AuNPs with 20 nm in diameter exhibited maximum inhibitory effect. In addition, AuNP with bare surface was found to be essential for the inhibitory effect on HB-GFs. Further, AuNPs have been reported to block of MAPK pathway in tumor cells which lead to the inhibition of epithelial to mesenchymal transition (EMT) and thence, the process of metastasis [51, 52].
AuNP has also been used as the carrier tool for drug delivery. It has been used to deliver an anti-EMT agent, Quercetin (Qu) and AuNP-Qu was found to be more effective when compared to free Qu, in inhibiting cell migration in MDA-MB-23 and MCF-7 cell lines [53]. In addition, recombinant human endostatin (rhES), an anti- angiogenic molecule, which in conjugation with AuNP-PEG (rhES-AuNPs-PEG), when administrated, targeted tumor cells more efficiently and exhibited better performance when compared to rhES. Moreover, the administration of rhES-AuNPs-PEG in combination with 5-flouro uracil (5-FU) facilitated improved localization of 5-FU on to the tumor site with subsequent reduction in tumor size than that in case of mono therapeutic administration of 5FU [54].
Silver NPs (AgNPs) have been reported to inhibit VEGF induced cell proliferation, migration and tube formation in bovine retinal endothelial cells (BRECs). It has also been reported to inhibit vessel formation in matrigel plug assay system. AgNP mediated anti angiogenic effect was found to involve negative regulation of PI3K/Akt pathway [55, 56]. According to a different study, AgNP has been reported to exert anti angiogenic effect by inhibiting HIF-1 in a dose dependant manner [57].
In addition to metal NPs, NPs based on cationic polysaccharides like chitosan has also been explored for biomedical applications taking an advantage of their relatively low toxic nature and high biodegradability and biocompatibility. Chitosan NPs (CNPs) showed anti-cancer effect in the xenograft model of hepatocellular carcinoma by inhibiting the expression of VEGFR2 and thereby negatively regulating the process of tumor angiogenesis [58]. Further, CNPs in conjugation with Ursolic acid (CH-UA-NPs) have been shown to inhibit cell migration and tube formation in human umbilical vein endothelial cells (HUVECs)
Ruthenium modified selenium NPs (Ru-SeNPs) have also been reported to exhibit anti angiogenic properties, in CAM model as well as in HUVEC cells, mainly by inhibiting the phosphorylation of Akt, FGFR1 and Erk1/2. Further, it has been shown that SeNPs protected with Ru (II)-thiols (Ru-MUA@Se) was endocytosed by the cells by clathrin mediated mechanism [61]. SeNPs have also been used as a carrier tool for siRNA delivery. A pH sensitive, modified SeNP carrying VEGF-siRNA, namely, G2/PAH-Cit/SeNPs@siRNA, has been shown to exhibit high efficiency in terms of cellular uptake, drug release and gene silencing [62].
The cerium oxide NPs (CONPs) have been reported to exhibit anti-oxidant activity and they are characterized by a cerium core and a shield with an oxygen lattice. Chen et al., have shown that CONPs are capable of inhibiting reactive oxygen species (ROS) induced angiogenic signaling pathways [63]. In addition, the nanoceria conjugated with heparin was reported to inhibit the proliferation of human coronary artery endothelial cells (HCAECs) in a better way than that by unconjugated nanoceria [64]. Nanoceria has also been reported to inhibit the proliferation of ovarian cancer cells in xenograft model
Silica based NPs have also been reported to exhibit anti angiogenic properties. Silicate NPs (SiO2 NPs) have been reported to inhibit VEGFR2 phosphorylation and ERK1/2 activation in human micro vascular retinal endothelial cells (HMRECs), thereby inhibiting angiogenesis [68]. Mesoporous silica based nanoparticles (MSNs) have been used as a vehicle for the targeted delivery of chemotherapeutic agent, doxorubicin hydrochloride (MSNs@DOX). MSNs@DOX has been reported to suppress the metastasis of lung cancer cells by inhibiting VEGF induced angiogenesis [69]. Further RGD (Arg-Gly-Asp) modified MSN has been used as a carrier tool for the targeted delivery of anti-angiogenic agent, NAMI-A [70].
Further, MoS2 nanoflakes containing ZnO NPs were found to inhibit tumor growth in
Applications of nanomaterials in anti-tumor therapy. Many candidate nanomaterials possess intrinsic anti-angiogenic property and few could be used as vehicles for targeted drug delivery. Nanoparticles encapsulated/conjugated with anti- angiogenic drugs or nanoparticle based anti-angiogenic scaffolds, when administrated in in vivo models, precisely target tumor vasculature and inhibit tumor growth.
Cardio vascular diseases (CVDs), which refer to a class of ailments encompassing coronary artery disease (CHD), peripheral arterial disease, cerebrovascular disease etc., account for the leading cause of death worldwide [74, 75]. Atherosclerosis is the most prevalent pathology behind CVDs, which involves the local accumulation of cholesterol within the walls of medium and large arteries leading to the emergence of atherosclerotic plaque [76, 77]. The process of angiogenesis has been implicated to play key role in plaque growth and intra plaque hemorrhage leading to plaque rapture [78, 79]. The application of nanomaterials has found its way in the diagnosis as well as treatment of CVDs. Integrin αvβ3 has been found to be over expressed in ECs actively involved in angiogenesis, thus, it has been targeted using NPs for CVD diagnosis [80]. For instance, in a murine model of hind limb ischemia, 76Br- labeled multivalent dendrimers conjugated with integrin αvβ3 targeting peptides, were utilized for the detection of angiogenesis by positron emission tomography-computed tomography (PET-CT) [81]. In a different experiment using murine model of hind limb ischemia, a natriuretic peptide receptor C- targeted, 64Cu labeled NP probe was used for the detection of angiogenesis [82]. Further, gadolinium-loaded perfluorocarbon (PFC) NP conjugated with a vitronectin antagonist peptide mimic, has been suggested to be a promising candidate for the detection of atherosclerotic lesions [83]. In addition, PFC NPs incorporated with anti-angiogenic drug, Fumagillin, have been implicated for the treatment of plaque angiogenesis [84].
Wounds are the disruption of the normal physiology of the skin, mucosal surfaces or organs, which occur as a part of a disease or etiology. The process of wound healing is divided into four distinct stages: hemostasis, inflammation, proliferation, and tissue remodeling. Injuries that show delayed healing up to 12 weeks after the initial insult are termed chronic wounds, often it happens because of various reasons such as persistent pathological inflammation [85], complications of ischemia, diabetes mellitus, or chronic venous insufficiency [86]. The application of growth factors has been employed to improve wound healing by promoting angiogenesis, but it possessed some drawbacks like rapid degradation of the candidate growth factors and the lack of controlled and localized delivery system.
Different NPs have been reported to promote wound healing, and many of them were implicated as drug carriers. Studies have shown that different metal ions-based nanomaterials possess the ability to promote angiogenesis and thereby induce wound healing [87, 88]. The metal ions such as Sr2+ and Co2+ when combined with nano bioactive glass showed pro angiogenic activity [89]. Colloidal AuNPs have been widely studied for biomedical applications due to their unique surface characteristics as well as optical and electronic properties [90]. AuNPs combined with epigallocatechin gallate and α-lipoic acid, reduced oxidative stress and inflammation and augmented angiogenesis, which led to cutaneous wound healing in rodent models [91]. The increased surface area of spherical AuNP helps in electron acceptance and also in scavenging reactive oxygen species that cause oxidative stress and impaired wound healing [92]. Formulation of AuNPs and scrambled peptides were reported to be suitable for angiogenic modulation in
Low expression levels of angiogenic growth factors lead to impaired angiogenesis and wound healing. Heparin mimetic peptide nanofiber scaffolds have been used to overcome this situation, which showed improved vascular development associated with enhanced VEGF production in the treated animals. Also, hierarchically micro-patterned nanofibrous scaffolds with a surface modified nanosized bio-glass have been implicated in improving wound healing [95]. Xie et al. have developed an electrospun fiber nano composites containing different components such as antibacterial polymer chitosan, poly (ethylene oxide), VEGF and PDGF-BB loaded poly (lactic-co-glycolic acid) NPs. They have demonstrated that the application of such a nano composite would prevent bacterial attack in the vicinity of wound. In addition, they have demonstrated that the nano composite facilitated the early delivery of VEGF from the nanofiber and sustained delivery of PDGF-BB from the NPs, thereby accelerating tissue regeneration and remodeling in a full-thickness rat skin wound model [96]. Lino et al. have shown that light-responsive plasmonic gold nanocarrier could be used as a carrier vehicle for the delivery of microRNAs such as miR-302a and miR-155, which regulated the proliferation and survival of ECs thereby promoting wound healing [97].
Carbon nanotubes were functionalized with different side-chain moieties and they were applied for diagnosis as well as drug delivery purposes [98]. It has been shown that the Multi-Walled Carbon Nanotube (MWCNT) supports angiogenesis as the macrophages engulfing MWCNT, produce angiogenic cytokines such as VEGF and MMP9 [99]. Liu et al. have constructed a composite scaffold of VEGF165 loaded functionalized MWCNT, for the prolonged and sustained delivery of VEGF165, and it promoted tissue remodeling and repairing in the
Graphene based NPs have also been implicated to have massive applications in angiogenesis-based therapeutics [101]. Graphene, graphene oxide (GO) and reduced graphene oxide (rGO) have received great attraction as inorganic additive in biopolymers for developing biomaterial composites [102]. The Gelatin-methacryloyl (GelMA) hydrogel containing rGO has been indicated to promote cell proliferation and migration in
Pro-angiogenic nanomaterials promote wound healing. Nanomaterials like cerium oxide nanoparticles, zinc oxide nanoflowers, multi walled carbon nanotubes, reduced graphene oxide nanoparticles and metal ion based nanoparticles like strontium ions and cobalt ions, promote wound healing in different in vitro and in vivo models by promoting the process of angiogenesis.
Diabetic retinopathy (DR) is one of the critical leading causes of blindness and it is a secondary complication associated with Diabetic Mellitus. Diabetes affects the entire neurovascular regions of the retina, with ongoing neurodegeneration, gliosis, neuroinflammation, edema, angiogenesis, and fibrosis [106]. The changes in the vasculature cause perceptible abnormality in vision and lead to blindness. VEGFA, which gets upregulated in response to hypoxia, plays a central role in the initiation of DR. In addition to that, MMP9 has also been implicated to play key role in the onset and severity of DR [107].
The Age-related macular degeneration (AMD) is another complication where pathological angiogenesis is involved. AMD has been classified into two types. The type of AMD which is characterized by yellowish deposits in the macula is known as the Dry AMD, whereas, the AMD with characteristic choroidal neovascularisation (CNV) is termed as the wet type or neovascular AMD [108].
Laser photocoagulation and multiple intra ocular injections are the treatment strategies adopted for the diseases that affect the vascular structure of the posterior eye. It has complications like the destruction of healthy tissues. Though ‘introducing protein drugs’, was put forth as one of the treatment strategies, it possessed drawbacks like drug instability due to proteases action followed by drug injection. It therefore warranted novel treatment strategies to conquer these drawbacks. So, in an effort to develop alternative therapeutic strategies for ocular diseases, the efficacy of different candidate NPs, exhibiting innate anti angiogenic property or possessing the ability to carry drug, growth factors etc., to specific tissue sites, have been tested by different groups [109, 110].
The AuNPs, as mentioned earlier, possess anti angiogenic properties in addition to their unique electronic, biocompatible, and molecular-recognition properties [111]. It has been reported to induce the nano structural reorganization of VEGFR2 in HUVECs and consequently suppressed angiogenesis [112]. AuNPs have also been reported to suppress VEGF induced cell migration by negatively regulating the phosphorylation of Akt and eNOS in retinal endothelial cells [113]. It has also been reported to obstruct the proliferation of VEGF treated retinal endothelial cells by suppressing Src signaling pathways [114].
Kringle 5 (K5), a proteolytic fragment of plasminogen possessing 80 amino acids, has been shown to be highly effective in the inhibition of EC growth [115]. It has also been reported to inhibit ischemia-stimulated retinal neovascularization in the oxygen-induced retinopathy (OIR) model [116]. But it possessed the drawback of a short life span. An expression plasmid of K5 was encapsulated with PLGA polymer to form nanoparticles (K5-NP) which effectively inhibited VEGF expression and attenuated ischemia-induced retinal vascular leakage and retinal neovascularization in the OIR rat model [117]. Biodegradable NPs loaded with Fenofibrate (Feno-NPs) have been reported to be particularly useful for the targeted delivery and treatment of DR and neovascular AMD. Fenofibrate is a peroxisome proliferator-activated receptor α (PPARα) agonist, which is effective against DR. In diabetic rat models, at 8 weeks after the administration of Feno-NP by one intravitreal injection, the vascular leakage in the retina was found to be reduced. In addition to that the retinal leukostasis was inhibited, and further, the expression of VEGF and ICAM-1 were down regulated [118].
Octreotide (OCT), an analog of somatostatin, is an established neuroprotective and anti-angiogenic agent that targets VEGF. The intra ocular delivery of OCT combined with Magnetic NPs (MNP-OCT) has been suggested to improve the half-life and bio activity of OCT [119]. Polliner et al. have checked the possibility of receptor mediated targeting of NPs to capillary endothelial cells in the retina, and they have demonstrated that Cyclo (RGDfC)-modified QDs specifically bind to the αvβ3 integrin receptors on the ECs and the cellular uptake mediated by receptor binding led to the accumulation of the NPs in the choriocapillaris and intraretinal capillaries [120].
Yandrapu et al. have formulated ‘Nanoparticles in Porous Micropaticles (NPinPMP)’, by encapsulating bevacizumab coated poly lactic acid NPs into porousifying PLGA microparticles (NPinPMP) using supercritical carbon dioxide (SC CO2). Bevacizumab is a protein drug used to treat neovascular AMD and it was necessary to inject once in a month intravitreally. The
Likewise, Luo et al. have used, biodegradable PLGA nanoparticles conjugated with integrin-binding linear RGD peptide, as a carrier tool for the delivery of recombinant tFlt23k intraceptor plasmid possessing VEGF binding domains. The nontoxic RGD-functionalized NP delivery system was observed to be getting targeted directly to the choroidal neovascularization lesions after intravenous injection, and exhibited excellent vision restoration in both primate and murine AMD models [122].
Celecoxib is a cyclooxygenase-2 inhibitor, exhibiting anti-inflammatory and anti-angiogenic properties. Celecoxib-loaded poly (ortho ester) NPs were found to be highly effective against AMD and DR [123]. Interleukin-12 (IL-12) has been reported to exhibit anti-angiogenic property by reducing the levels of MMP9 and VEGFA [124]. Zheng and colleagues combined IL-12 with PLGA nanoparticles (IL-12-PNP) and proved it to be exhibiting better efficacy in terms of inhibition of VEGFA and MMP9 expressions in DR mouse retina and rat ECs. Further, the intra ocular administration of IL-12-PNPs showed reduced retinal damage in mice model with DR [125].
Osteogenesis is referred to the process of regeneration of bones, which involves multiple steps such as the activation, migration and differentiation of different cell types [126]. The process of angiogenesis is crucial for the supply of growth factors, hormones, cytokines, chemokines, and metabolites required for osteogenesis. Any aberrancy associated with the vascular supply to the bone tissues would lead to different pathologies such as osteonecrosis [127], osteomyelitis [128], and osteoporosis [129, 130]. Discrepancy in angiogenesis has also been reported as one of the main reasons for the failure of osteogenesis after implantation. VEGF and HIFα are the major angiogenesis related factors that promote osteoblast differentiation and osteogenesis. So, it has been suggested that restoring angiogenesis would promote bone function and defect repair in pathologies with impaired osteogenesis.
Many candidate nanomaterials have been reported to be effective in improving the repair of bone tissues [131]. For example, synthesized chitin–CaSO4–nano-fibrin based injectable gel system showed enhanced osteo-regeneration via enhanced angiogenesis [132]. Further, the β CaSiO3/PDLGA composite has been reported to induce the phosphorylation and activation of Akt and eNOS respectively in HUVECs with a resultant increase in the synthesis and release of NO and VEGF. Further the bone regeneration study in the rabbit femur defect model using β CaSiO3/PDLGA composite has shown enhanced angiogenesis and osteogenesis [133]. Nano-hydroxyapatite has been reported to regulate the PI3K/Akt pathway for inhibiting migration and tube formation in HUVECs via inhibiting NO synthesis and eNOS phosphorylation [134]. Similarly, calcium phosphate combined with electro spun poly (lactic acid) has been reported to promote VEGF expression in endothelial cells. It has also been reported to support vascular development and bone regeneration when injected subcutaneously in mice, by promoting the expression of proangiogenic factors like VEGF, IGF-2, GM-CSF, IL-1 beta, IL-6, IL-12p70 etc. [135]. Similarly, Nano bioactive glass, characterized by higher surface area and three-dimensional channel structure, is another material that could promote angiogenesis and bone regeneration [136, 137].
Nanomaterials can also act as carrier tools for different pro angiogenic small molecules and proteins like deferoxamine, adrenomedullin, VEGF etc. For example, Mesoporous silicate nanoparticles (MSNs) incorporated-3D nanofibrous gelatin (GF) scaffold has been employed for the dual-delivery of bone morphogenetic protein-2 (BMP2) and deferoxamine (DFO). DFO, being a hypoxia-mimetic drug, could trigger the stabilization of HIF-1α, and initiate subsequent angiogenesis. Further, it has been shown that DFO could significantly enhance BMP2 induced osteogenic differentiation in mouse and human stem cell models [138].
Ionic components have been utilized for the modification of vascularized bone tissue engineering scaffold. The Copper based nanomaterials could promote the expression level of VEGF, which in turn promoted the proliferation of ECs. Nano-structured surfaces on the Hydroxyapatite scaffolds in copper ion (Cu2+) containing solutions under hydrothermal conditions could affect EC proliferation. Further, the nano-structured surfaces on the Hydroxyapatite scaffolds, promoted angiogenesis and bone regeneration. Dexamethasone (DEX), an osteogenic inducer combined with biphasic calcium phosphate nanoparticle (BCP NPs) scaffold, was found to induce the expression of VEGF and VEGFR2 and supported bone regeneration. The micro-grooves present in the scaffolds managed the assembly of HUVECs into tubular structures and promoted angiogenesis [139]. The gene encapsulated magnetic microspheres have also been used as a promising delivery system. For instance, introduction of VEGF165 with superparamagnetic (nano-Fe3O4) chitosan, induced
The AuNPs have also been reported to induce angiogenesis during osteogenesis. AuNPs exhibited differences in angiogenic activity based on their surface charges and the presence of functional groups. The Gene profiling data revealed that in comparison with the cells (hMSCs) treated with AuNPs possessing amine or hydroxyl functional groups (AuNPeNH2 or AuNPeOH), the cells treated with carboxyl group containing AuNPs (AuNPeCOOH) showed augmented expression levels of TGFβ and FGF-2, which in turn promoted cell proliferation over osteogenic differentiation [141].
Nerve tissue degeneration is a critical clinical challenge that leads to diseases like trauma or permanent paralysis, so research advancement in the field of nerve tissue regeneration is quite necessary. In the recent years, the applications of nanomaterials have received much attention from the research community focusing on nerve tissue repair.
The process of angiogenesis plays key role in supplying nutrients to the nerve tissue which in turn helps to repair segmental nerve defects. Recently, Lopez-Dolado et al. have designed a 3D scaffold containing partially reduced graphene oxide, which when implanted in the injured site in the spinal cord of a rat model, a remarkable induction in angiogenesis and axon regeneration was observed [142].Further, GO/polycaprolactone (PCL) nano scaffolds have been implicated to promote angiogenesis by modulating Akt-eNOS-VEGF signaling pathway and it facilitated peripheral nerve regeneration
In addition, Xu et al. have formulated an acellular spinal cord scaffold (ASCS), namely, V-ASCS, for the sustained delivery of VEGF, and it was composed of VEGF165 encapsulated PLGA nanoparticles conjugated with ASCS. When V-ASCS was implanted at the injury site in a rat spinal cord hemisection model, it rendered significant progress in neovascularization [144]. Wen et al. fabricated a hyaluronic acid scaffold with brain-derived neurotrophic factor and VEGF loaded PLGA microspheres, which promoted angiogenesis and nerve fiber regeneration when implanted at the injured site in the spinal cord of rat model [145]. Yu and his co-workers have formulated PLGA microspheres encapsulated with VEGF, angiopoietin-1 and bFGF, and these angiogenic microspheres could release the angiogenic factors in a sustained fashion, which then induced angiogenesis and neurogenesis when administered at the injured site in the spinal cord of rat model [146].
Jian et al. have fabricated a nanohybrid hydrogel containing sulfated glycosaminoglycan-based polyelectrolyte complex nanoparticles (PCN), and it could accelerate neurogenesis and angiogenesis in
Delivery of superparamagnetic iron oxide nanoparticle labeled Endothelial progenitor cells (EPCs) was found to induce the formation of vessel-like structures by the production of VEGF and FGF [149]. Similarly, superparamagnetic iron oxide (SPIO)-Au core-shell NPs incorporated with nerve growth factor (NGF) have been implicated to promote neuron growth and differentiation [150].
Aberrancy associated with angiogenesis pave the way for the progression of a number of diseases like tumor, cardio vascular diseases, diabetic retinopathy, age related macular degeneration etc. So, targeting angiogenesis presents itself as one of the key therapeutic strategies to tackle such complications. The currently available therapies though beneficial, do possess some limitations like acquisition of drug resistance by cells, fast decay of protein drugs by protease action, off target effects leading to decreased drug efficacy etc. Different candidate nanomaterials were implicated to possess anti- angiogenic properties, which were tested
Nanomaterial based formulations for the treatment of pathological conditions with aberrant angiogenesis. Abnormal angiogenesis promotes the progression of different diseases like tumor, cardiovascular disease, chronic wounds, diabetic retinopathy, wet type age related macular regeneration, bone and nerve tissue degeneration etc. nanomaterials possessing intrinsic pro- or anti- angiogenic property could be utilized individually or as a part of biodegradable polymer based-scaffolds for the treatment of such disorders. Different candidate nanoparticles with surface modifications with peptides like arginine-glycine-aspartate (RGD) and vascular endothelial growth factor (VEGF), could be utilized as carrier tools for targeted drug delivery.
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