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‘The FANG’S OF THE SERPENT ARE MAKING THEIR ‘MARK’’; Microneedles: A smart approach and increasing potential for transdermal drug delivery system

Ezekiel 33:2-6

“”When I bring the sword upon a land, and the people of the land take a man from their territory and make him their watchman,

3, when he sees the sword coming upon the land, if he blows the trumpet and warns the people,

4, then whoever hears the sound of the trumpet and does not take warning, if the sword comes and takes him away, his blood shall be on his own head.

5, He heard the sound of the trumpet, but did not take warning; his blood shall be upon himself. But he who takes warning will save his life.

6, But if the watchman sees the sword coming and does not blow the trumpet, and the people are not warned, and the sword comes and takes any person from among them, he is taken away in his iniquity; but his blood I will require at the watchman”s hand.” (Ezekiel 33:2-6)

Revelation 19:20 

And the beast was taken, and with him the false prophet that wrought miracles before him, with which he deceived them that had received the mark of the beast, and them that worshipped his image. These both were cast alive into a lake of fire burning with brimstone.

Revelation 14:11

And the smoke of their torment ascendeth up for ever and ever: and they have no rest day nor night, who worship the beast and his image, and whosoever receiveth the mark of his name.

Pastor Mike Taylor;

Each of us are watchmen on the wall. If you stand behind a pulpit or preach to a congregation in whatever media you use, you have a responsibility to warn those who are in danger of hell fire and all that it represents. God does not send anyone to hell, as it is a decision that each of us must make, but the Word of God must start with men and women who are commissioned by God to take the Word of Truth to those who are in their sins.

Whether a minister believes he is a watchman or not, he is commissioned by God to spread the Gospel to the lost. He is to preach the penalty of sin. He is to abandon a feel good “gospel”, prosperity gospel, or a social speech of humanism and being just a “good citizen”. This won’t save anyone. It will not warn those who are walking the wide road and gate to destruction, but will only placate them that they are OK…they are not OK, as they do not have Jesus in their hearts. It is a minister’s job to take the message of salvation to his congregation, his community and the rest of the world.

Jan Markell, Olive Tree Ministries;

Prepping for ‘Mr. Fix-It’

 Society is being prepped for the Antichrist, and as prophecy-loving believers try to warn, the words are falling on a lot of deaf ears.

 The stage is being set for a closing act. The players are getting into their proper positions. Heads of state are meeting to plot and scheme and deny even more rights. In places like Australia, Lithuania, and Austria, good people are enemies of the state even though they are upstanding citizens.

 World leaders have no comprehension they are majoring in minors. To them, it makes perfect sense to obsess over carbon emissions. During the Tribulation, this will fade from their memories as they cope with Seals and Trumpets and Bowls. These will spark “climate change” they cannot imagine!

 Most receiving this newsletter are “watchmen.” Ezekiel 33 tells us that if you don’t warn, the blood is on your hands, so you cannot be silent.

 Brace yourself to be shocked daily by things you read and watch. Satan is getting more active, and wickedness is rising, so God’s people must shine more brightly.

 But for the believer, a glorious event will happen soon. It is known as the Rapture of the Church. It is any day. Any hour. Any minute. So don’t grow weary!

 And yes, if a believer is a Rapture skeptic, they get the surprise of their life someday soon. Then you’ll have the privilege of saying, “I told you so.”

 Won’t that be a glorious day?

Pastor Greg Laurie; Harvest Ministries

“God promises this in the book of Revelation, and He also gives us a promise of global peace. The Antichrist, however, will bring pseudo peace. During the first three-and-a-half years of the seven-year Tribulation, he will come across as a good guy. But in reality, he will be a bad guy. And the Scriptures say that he will use peace to deceive many. Ultimately, once Antichrist is taken out of the way, God will bring global peace.”

Paul Rolland, Night Watchman, Night Watchman Ministries

‘The FANG’S OF THE SERPENT ARE MAKING THEIR ‘MARK’’; Microneedles: A smart approach and increasing potential for transdermal drug delivery system

Author links open overlay panelTejashreeWaghuleaGautamSinghviaSunil KumarDubeyaMurali MonoharPandeyaGauravGuptabMahaveerSinghbKamalDuacde

A Department of Pharmacy, Birla Institute of Technology & Science (BITS), Pilani Campus, Pilani, Rajasthan, 333031, India

B School of Pharmaceutical Sciences, Jaipur National University, Jagatpura, 302017, Jaipur, India

C Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, Ultimo, NSW, 2007, Australia

D School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW, 2308, Australia

E Priority Research Centre for Healthy Lungs, Hunter Medical Research Institute, Lot 1 Kookaburra Circuit, New Lambton Heights, Newcastle, NSW 2305, Australia

Received 12 July 2018, Revised 30 September 2018, Accepted 14 October 2018, Available online 9 November 2018.

Abstract

The most widely used methods for transdermal administration of the drugs are hypodermic needles, topical creams, and transdermal patches. The effect of most of the therapeutic agents is limited due to the stratum corneum layer of the skin, which serves as a barrier for the molecules and thus only a few molecules are able to reach the site of action. A new form of delivery system called the microneedles helps to enhance the delivery of the drug through this route and overcoming the various problems associated with the conventional formulations. The primary principle involves disruption of the skin layer, thus creating micron size pathways that lead the drug directly to the epidermis or upper dermis region from where the drug can directly go into the systemic circulation without facing the barrier. This review describes the various potential and applications of the microneedles. The various types of microneedles can be fabricated like (5) solid, dissolving, hydrogel, coated and hollow microneedles. Fabrication method selected depends on the type and material of the microneedle. This system has increased its application to many fields like oligonucleotide delivery, vaccine delivery, insulin delivery, and even in cosmetics. In recent years, many microneedle products are coming into the market. Although a lot of research needs to be done to overcome the various challenges before the microneedles can successfully launch into the market.

1. Introduction

Hypodermic needles and topical creams are most commonly used when it comes to delivery of the drug through the skin. Needles are less accepted by patients due to pain associated with them and topical creams show less bioavailability. Skin serves as the major barrier for delivering drug through the topical route. Skin is made up of three main layers-the outermost stratum corneum, middle epidermis and the thickest of all, dermis. The stratum corneum layer behaves like a major barrier as it allows only certain molecules like lipophilic and low molecular weight drugs to pass through it. The relatively less permeability of the layer presents many problems in designing topical formulation [1,2]. Various topical or transdermal delivery systems have been investigated for improving drug permeation through the skin like nanocarrier loaded topical creams, transdermal patches, and microneedles [3,4].

The microneedles (MNs) have been studied by various researchers for delivering drug through the transdermal route and for overcoming the limitations of the conventional approaches. Microneedle device consists of needles of micron size, which are arranged on a small patch. Considering the problems of the hypodermic needle and the transdermal patch, microneedle drug delivery system was developed and is thought to be the hybrid of both. The major problem associated with transdermal technology is that many of the drugs are not able to cross the skin at the required rate necessary for the therapeutic action. Researchers have developed a refined technology using microneedles, which allow hydrophilic high molecular weight compounds to enter into the stratum corneum. Administration of drugs using the microneedle device allows the drug molecules to cross the stratum corneum layer, thus allowing more drug molecules to enter the skin. The characteristic features of this technology are the (5) faster onset of action, better patient compliance, self-administration, improved permeability and efficacy [2]. In addition to improved therapeutic advantages, microneedles give highly accurate reproducible results with minimum inter-subject variability in bioavailability. Though it has many advantages it also possesses some limitations. There is the possibility of skin irritation or allergy to sensitive skin. Since the needle size is very small and thinner as compared to the thickness of hair, breaking of microneedle tips may take place which if remained inside the skin, can cause problems. These limitations are very rare and can be overcome with advanced material selection for microneedles. The main objective of developing this technology is to create larger transport pathway of micron size which is larger than molecular dimensions and smaller than holes by hypodermic needles, to disrupt the stratum corneum to allow large molecules to pass through thus increasing the permeability [5]. Conventional methods like electric methods- iontophoresis and electroporation, chemical/ lipid enhancers create pores of nanosize which improve the permeability up to some extent but fail for large molecules [6]. A comparative discussion is compiled for various transdermal drug delivery systems in Table 1. The drug delivery by various transdermal systems is presented in Fig. 1. The topical cream spreads only on the skin surface. It has been reported that only 10–20% of total drug loaded in cream is being permeated through the skin [3]. In case of a transdermal patch, the drug has to pass the stratum corneum barrier thus it also shows less bioavailability. Addition of permeation enhancer in the transdermal patch can improve the drug permeation but up to a very limited extent [4]. The hypodermic needle goes deep into the dermis where pain receptors are present. Thus it can deliver 90–100% of the loaded drug but it is very painful which results in poor patient compliance. Microneedle patch bypasses the stratum corneum barrier and delivers the drug directly into the epidermis or upper dermis layer which delivers 100% of the loaded drug without pain [5].

2. Mechanism of drug delivery

The delivery of the drug through the topical route follows the diffusion mechanism. In the microneedle drug delivery system, the skin is temporarily disrupted. A microneedle device is made by arranging hundreds of microneedles in arrays on a tiny patch (the same as that of a normal transdermal patch available in the market) in order to deliver sufficient amount of drug to give a required therapeutic response. It pierces the stratum corneum thus bypassing the barrier layer. The drug is directly placed in the epidermis or upper dermis layer which then goes into the systemic circulation and shows a therapeutic response on reaching the site of action [6,7]. Mechanism of drug delivery through microneedles is depicted in Fig. 2.

Fig. 2. Mechanism of drug delivery by microneedle device: (1) Microneedle device with drug solution; (2) Device inserted into the skin; (3) Temporary mechanical disruption of the skin; (4) Releasing the drug in the epidermis; (5) Transport of drug to the site of action.

3. Dimensions of microneedles

Microneedles can be formulated in varying sizes depending on the type of microneedle and the material used. Since the epidermis is up to 1500 μm thick so the needle length of up to 1500 μm is sufficient to release the drug into the epidermis. Needles larger in length and thicker in diameter can go deep into the dermis, damage the nerves and cause pain [5]. Mostly they are 150–1500 microns long, 50–250 microns wide, and have 1–25 microns tip thickness. As discussed earlier the need for microneedle device is to create micron size transport pathway, the diameter of needles is kept between few microns. Microneedle tips can be (5) cylindrical, triangular, pointed, pentagonal, octagonal and are available in many more shapes [7].

4. Microneedle fabrication material and its properties

4.1. Silicon

The first microneedle was made from silicon in the 1990s [6]. Silicon is anisotropic in nature and has a crystalline structure. Its properties depend on the alignment in the crystal lattice, which shows different elastic moduli (50 to 180 GPa) [[8][9][10]]. Its flexible nature allows producing needles of different sizes and shapes. Its attractive physical properties make it a versatile material. Silicon substrates can be precisely manufactured and are capable of batch production. The cost of silicon and its time-consuming complex fabrication process limits its use in microneedle. In addition, there are some biocompatibility issues, as silicon is brittle, some part may break and remain in the skin thus causing some health issues [8].

4.2. Metal

The main metals used are stainless-steel and titanium. Palladium, nickel, palladium-cobalt alloys are also used [11]. They have good mechanical properties and good biocompatibility. Metals are strong enough to avoid breaking, thus more suitable as compared to silicon for microneedle production. The first metal used in the production of microneedle was stainless steel [12]. Titanium is a good alternative to stainless steel [8,13].

4.3. Ceramic

Alumina (Al2O3) is mainly used because of its chemical resistance. It forms a stable oxide because of the highly energetic ionic and covalent bonds between Al and O atoms [14]. Other types of ceramics used are calcium sulfate dihydrate [Gypsum (CaSO4 0.2H2O)] and calcium phosphate dihydrate [Brushite (CaHPO4.2H2O)] [5]. In recent years an organically modified ceramic called Ormocer® has been used. It is a three-dimensionally cross-linked copolymer [15]. A polymer with different properties can be produced by using different organic units during polymerization. Mainly they are produced using a micro-molding technique. Ceramic slurry is cast into a micro-mold. Micro-moulding techniques are cheaper processes, and also have the potential for scale-up [8].

4.4. Silica glass

Varying geometries can be produced on small scale using glass. Silica glass is physiologically inert but brittle in nature [16]. Borosilicate glass which is made up of silica and boron trioxide is more elastic. They are mostly fabricated manually, thus are less time efficient [17]. Glass MNs are not used now commercially, but only for experimental purposes [8].

4.5. Carbohydrate

Maltose is one of the most common sugars used [18]. Other sugars, such as mannitoltrehalose, sucrose, xylitol and galactosepolysaccharides can also be used [19]. Carbohydrate slurries are moulded by making use of silicon or metal templates. The drug-loaded carbohydrate mixture is casted into the moulds to get the microneedles [20]. The time-based dissolution of carbohydrate regulates the drug release inside the skin. Carbohydrates are cheap and safe for the human health but degradation at high temperatures makes the fabrication process difficult [8].

4.6. Polymer

A wide variety of polymers including poly (methyl methacrylate) (PMMA) [21], polylactic acid (PLA) [22], poly (lactic-co-glycolic acid) (PLGA) [23], polyglycolic acid (PGA) [17], poly (carbonate) [24], cyclic-olefin copolymer, poly (vinylpyrrolidone) (PVP) [25], poly (vinyl alcohol) (PVA) [25], polystyrene (PS) [26], poly (methyl vinyl ether-co-maleic anhydride) [27], SU-8 photoresist [28] are reported for microneedles preparation. Mostly, dissolving or biodegradable and hydrogel-forming microneedles arrays are made from these polymers. Microneedles fabricated with these polymers have less strength than other materials but are tougher than glass and ceramics [8,9].

5. Types of Microneedle

Different types of microneedles fabricated and investigated for their application in drug delivery are (5) solid, coated, dissolving, hollow, and hydrogel microneedles. Different types of microneedles with their unique properties are displayed in Fig. 3. Each type of microneedle has its own way of delivering the drug into the epidermis. Some are used just to create pores in stratum corneum, some are precoated with the drug solution on their surface, some are dissolvable and some are prefilled with the drug solution [[29][30][31][32]].

Fig. 3. Different types of microneedles (a) Solid microneedles use poke with patch approach, are used for pre-treatment of the skin; (b) Coated microneedles use coat and poke approach, an coating of drug solution is applied on the needle surface; (c) Dissolving microneedles are made of biodegradable polymers; (d) Hollow microneedles are filled with the drug solution and deposit the drug in the dermis.

5.1. Solid microneedles

Solid microneedles are mostly used for pre-treating the skin by forming pores. Pointed tips of the needles penetrate into the skin; create channels of micron size, through which the drug directly enters the skin layers on the application of a drug patch, thus increasing the permeation. The drug is taken up by the capillaries to show a systemic effect. It can be used for a local effect also [29]. Solid microneedles deliver the drug with passive diffusion to skin layers [1,30]. Narayanan et al fabricated solid silicon long and tapered microneedles using tetramethylammonium hydroxide etching process. Microneedles with an average height of 158 μm and base width of 110.5 μm were successfully fabricated [33]. Later he also fabricated the gold-coated solid silicon microneedles with the dimension of 250 μm in height, the base width of 52.8 μm, the aspect ratio of 4.73, tip angle and diameter of 24.5° and 45 μm. The results demonstrated improved bioavailability and mechanical strength [34]. Li et al studied polylactic acid microneedles and found that biodegradable polymer solid microneedles have sufficient mechanical strength to pierce the stratum corneum and can enhance the absorption of the drug. The microneedles having 800 μm depth and density of 256 MNs per cm2 was found to enhance the drug permeation [35]. Stainless steel microneedles are also studied by various researchers. Enhanced delivery of captopril and metoprolol tartrate was studied after application of stainless steel MN arrays [1].

5.2. Coated microneedles

The microneedles are surrounded with the drug solution or drug dispersion layer [1]. Subsequent dissolution of drug from the layer takes place and the drug is delivered quickly. The amount of drug that can be loaded depends on the thickness of the coating layer and the size of the needle which is usually very less [29]. Baek et al loaded lidocaine on poly l-lactide (PLLA) microneedle arrays. The loaded lidocaine released rapidly in phosphate buffer saline and was found to be stable for 3 weeks [36]. Coated microneedle also explored for delivery of multiple agents through same formulation. Li et al coated each microneedle with different formulations and drugs thus allowing co-delivery of multiple agents with different properties. These delivered water soluble and water insoluble dyes simultaneously [37]. Chen and co-workers coated PLA microneedles with sulforhodamine B and found the drug delivery efficiency to be approximately 90%. The in-vitro studies in mice confirmed the continuous drug delivery [38].

5.3. Dissolving microneedles

Dissolving microneedles are fabricated with biodegradable polymers by encapsulating the drug into the polymer. After inserting microneedle in the skin, dissolution takes place which releases the drug. The application involves only a single step as the microneedle is not to be removed out after insertion as in other cases. The polymer gets degraded inside the skin and controls the drug release. The bio-acceptability and dissolution of the polymer inside the skin make it one of the best choices for long-term therapy with improved patient compliance [1]. Effective needle drug distribution is an important factor which faces problems while developing dissolving microneedles. Hence, polymer-drug mixing is a critical step in such fabrication [30]. Chen and his group developed tip dissolving microneedles which showed rapid and efficient drug delivery without skin irritation [39]. Dissolving microneedles take time to dissolve and complete insertion is difficult. Zhu et al developed rapidly separating microneedles mounted on solid microneedles which gave sufficient mechanical strength to the microneedles and approx 90% delivery efficiency was observed in 30 s [40]. Wang et al introduced the addition of bubbles to the dissolving microneedles to prevent drug diffusion in the entire microneedles. These were found to achieve about 80% of drug delivery efficiency in 20 s [41]. Separable arrowhead microneedles were developed by Chu et al. Sharp polymer tips encapsulated with the drug were mounted on blunt metal shafts which separate or dissolve on insertion in the skin within a few seconds. These modifications in dissolving microneedles showed that possibilities of the rapid drug delivery with controlled release kinetics [42].

5.4. Hollow microneedles

Hollow microneedles have an empty space inside which is filled with the drug dispersion or solution. They have holes at the tips. On inserting into the skin, the drug is directly deposited into the epidermis or the upper dermis layer. Mostly it is used for high molecular weight compounds such as proteins, vaccines, and oligonucleotides [1]. The drug flow rate and release pressure can be adjusted if the drug is to be given by a rapid bolus injection. These microneedles are capable of administering a large dose of the drug as more amount of drug can be accommodated into the empty space inside the needle. Maintaining a constant flow rate is essential here [32]. Increase in the microneedle bore can increase flow rate but lead to reduced strength and sharpness. Sometimes a metal coat is applied on the microneedle to increase the strength of the microneedle but this can make the needles sharp [1]. Mishra et al developed hollow microneedles aligned on the silicon substrate having a length of 500–600 μm and 100 μm outer diameter. The flow rate of 0.93 μl s−1 was achieved at 2 K Pa pressure difference [43]. Maaden and co-workers fabricated fused silica hollow microneedles using hydrofluoric acid etching. These microneedles were able to inject very less amount of vaccine into the skin in an automated manner thus overcoming the drawbacks of the hypodermic needle [44]. Interestingly Suzuki and colleagues developed hollow microneedles which were mimicking the action of mosquitoes and the designed microneedles showed improved penetration in the skin [31].

5.5. Hydrogel-forming microneedles

This type of microneedle is recently developed. Super-swelling polymers are used to make microneedles. The polymers constitute the hydrophilic structure which makes it capable of taking up a large amount of water into their three-dimensional polymeric network. These polymers swell when inserted into the skin due to the presence of the interstitial fluid. This leads to the formation of channels between the capillary circulation and the drug patch. Before needling, these microneedles are just used to disrupt the skin barrier. On swelling, they behave as a rate controlling membrane. They have flexibility in size and shape. Easy sterilization and intact removal from the skin are the unique properties of such microneedles [45]. Migdadi et al studied hydrogel-forming microneedles to administer metformin transdermally so as to decrease the gastrointestinal side effects associated with the oral delivery. Results demonstrated the improved permeation and bioavailability of the drug with designed microneedles [46]. Cross-linked polymers are also utilized for fabricating swellable microneedles for drug delivery.

6. Methods of delivering drug

Various methods can be used to deliver the drug into the epidermis layer. One approach is to poke the skin with the microneedles to create holes, followed by removal of the microneedle and application of the drug-containing patch over it. This creates a direct transport pathway for a drug to travel into the skin. The electric field can be applied for better effect. The second approach is to cover the microneedle surface with a coating layer containing the drug. The coated microneedles are inserted into the skin where drug dissolution takes place from the coating [6]. The third approach is to dip the microneedles into the solution containing drug and scrape the needles on the skin. The drug is left behind into the abrasions. Another approach is to incorporate the drug into a biodegradable polymer and fabricate the microneedles from the mixture. One can design a hollow microneedle where the drug solution can be filled into the hollow space of the microneedles [8,34].

7. Fabrication techniques

The selection of fabrication or manufacturing method for microneedles depends on the type, geometry and the material of the microneedle [29]. Various techniques used for different type of microneedles are mentioned in Table 2 [[47][48][49]].

Table 2. Fabrication techniques for different types of microneedles [[47][48][49]].

8. Evaluation of microneedles

8.1. Characterization methods

The drug can be loaded onto or into the microneedles either in suspension/dispersion form or encapsulated form (liposomes, nanoparticles, nanoliposomes) [37]. The drug can be coated with the polymer solution or can be applied as a patch. Various physicochemical characterizations including particle size, polydispersity index, viscosity, and zeta potential can be evaluated for loaded drug depending on the type of formulation used in the microneedles [50]. Drug release, adhesion, permeation tests are performed for a patch which is applied after pre-treatment. The size, internal structure, and crystallinity of the liposomes or nanocarriers can be performed using dynamic light scatteringX-ray scattering, and transmission electron microscopy technique. Stability studies of drug dispersion and microneedles can be studied at a different temperature, pH and simulated in-vivo physiological conditions (cell line or tissues). Other tests like solubility studies, drug content, in-vitro release tests, and biocompatibility studies are also performed on designed microneedle [5,15].

8.2. Dimensional evaluation

Various methods are used to evaluate the needle geometry and to measure the tip radius, length, height of the microneedle. Most common methods are optical or electrical microscopy. Analysis of a 3D image gives a better picture of needle geometry and helps in quality control. Scanning Electron Microscope (SEM) and confocal laser microscope have been used for this purpose. SEM produces an image of a sample by making use of a focused beam of electrons which interact with the atoms in the sample while scanning and produce various signals which give information about sample surface topography and composition. Confocal laser microscope produces high-resolution images [51,52].

8.3. Mechanical properties or insertion forces

A microneedle must be sharp and slender enough so that it can easily penetrate into the skin and also be strong enough so that it does not break when inside the skin. Mechanical tests which are performed on microneedles are given in Table 3. Two important factors for a safe and efficient design of microneedles are the force at which the microneedle loses its structural integrity and the insertion force. The ratio of these two forces is called as the ‘safety factor’. The ratio is preferred to be as high as possible [53].

8.4. In-vitro skin permeation studies

Diffusion cell apparatus is used to find the permeation of the drug through the skin. Pig ear skin is mostly used in the experiment which is mounted between the receptor and donor compartment. The cumulative permeation profiles of microneedle treated and untreated skin are compared [54].

8.5. In-vivo animal model studies

Hairless rats can be used for the study. A suitable technique to anesthetize the animal shall be used. One of the parameters considered is trans-epidermal water loss (TEWL) which is measured before and after micro needling. Delfin Vapometer is used to measure this parameter [54].

9. Patient compliance and safety

9.1. Skin recovery process

When a microneedle device is inserted into the skin and removed after the treatment, it leaves behind holes of micron size. It may take time to reseal these pores. These holes need to be resealed quickly, otherwise may cause infection. The time taken by the skin to recover its barrier properties is important. Pore resealing can be studied by electrical impedance measurement. It can take 2–40 hrs to recover depending on whether the skin is occluded or not and also the geometry of the needle. TEWL and tissue staining can also be used to study pore resealing [29,30].

9.2. Skin irritation

The normally used transdermal injections even show a small swelling around the site. This is because the skin layer is disrupted while a foreign material is being inserted into the skin [29].

9.3. Skin irritation and infection

As the skin is exposed to various environmental stresses, skin carries various defense mechanisms to protect itself. In case of sensitive skin, use of microneedles can cause mild to moderate skin irritation or allergy. Redness, pain, swelling can be seen. Itching can cause patient discomfort [55]. Holes caused by inserting microneedles into the skin can be a site of infection unless the needles are sterile. Although the pores created by microneedles are very small as compared to that of a hypodermic needle, thus show less microbial penetration [29].

9.4. Pain

The microneedles do not reach the pain receptors which are deep into the dermis, thus cause less pain as compared to that of a hypodermic needle. The intensity of pain depends on the number of microneedles on a patch, length of the microneedle and the tip angle or needle shape [29]. Gill et al confirmed that microneedles cause less pain than a 26-gauge hypodermic needle. Lesser the microneedles length and number on the patch, less is the pain associated with the therapy [56].

10. Applications

10.1. Oligonucleotide delivery

Oligonucleotides are short DNA or RNA molecules. Delivering oligonucleotide to their intracellular site of action is difficult. Therefore various techniques to enhance the delivery were discovered. An attempt to deliver 20-merphosphorothioated oligodeoxynucleotide was made using the microneedle approach. Solid microneedles made up of stainless steel or titanium were tried to deliver oligonucleotides using the poke with patch approach. More amount of drug was found to reach the site of action as compared to the intact skin. Using iontophoresis along with microneedle approach gave better results than iontophoresis alone [2,57].

10.2. Vaccine therapy

A vaccine is a biological preparation. It provides active acquired immunity to a particular disease. Vaccine constitutes a killed or weakened form of disease-causing micro-organism, its toxins or one of its surface proteins. Vaccine therapy stimulates the immune system of the body and provides protection against the future micro-organism encounter. Microneedle approach was found to be effective in vaccine therapy [29,30].

DNA vaccine was delivered using microneedle. Immune responses seen were much better than that of the normal injections [58]. An attempt to develop a microneedle patch which can be used for administering influenza vaccine was also made [59]. A less dose is required when the drug is administered using hollow microneedles as compared to intramuscular injection. Administration of anthrax and rabies vaccine using hollow microneedles was also studied [8]. Ogai and colleagues fabricated hollow microneedles from poly-glycolic acid to enhance the vaccination efficiency by the intradermal route. The precise delivery of the drug in the upper dermis provides enhanced immunity. After the vaccination, the antibody titers were significantly higher with intradermal vaccination with microneedles as compared to subcutaneous injection on 15th day [60]. Dissolving microneedles were also investigated for intradermal vaccination [61].

10.3. Peptide delivery

Peptides are enzymatically degraded when administered through the oral route. Transdermal delivery avoids this but less amount of peptide is able to cross the skin. Peptide delivery through microneedles can help overcome poor skin penetration of the peptides. Desmopressin is a synthetic form of vasopressin, a potent peptide hormone. It is used to replace low levels of vasopressin. This medication is used to treat diabetes insipidusbedwetting in young children and hemophilia A. Use of microneedle approach to deliver desmopressin was studied which showed that microneedle delivery was safe and more efficient as compared to other routes [2]. Cyclosporin A is a water-insoluble and high molecular weight cyclic peptide which is used to treat various skin diseases. Dissolving microneedles containing cyclosporine A with the dimension of 600 μm in length and 250 μm wide were prepared by molding process. Fabricated microneedles with 10% cyclosporine A was pressed into the porcine skin for 60 min which showed dissolving of approx 65% of microneedle with 34 ± 6.5 μg drug delivery [62]. In one study, GAP- 26 which is a gap junction blocker loaded polyethylene glycol diacrylate based microneedles were fabricated by Liu et al for delivering peptides through swelling effect. The designed microneedles showed improved permeation of loaded peptide which confirmed with the inhibition of the proliferation of keloid fibroblasts and the collagen I expression [63].

10.4. Hormone delivery

Insulin is a peptide hormone. The medication is used to lower the high blood sugar levels. Delivering insulin using microneedle was found to lower blood glucose levels more efficiently [64]. Li et al fabricated solid microneedles and studied the effect on blood glucose levels in diabetic mice on delivery of insulin. The results demonstrated the reduced blood glucose level to 29% of the initial level at 5 h which confirmed the improved permeability of insulin to the skin using microneedle [35]. Ye and co-workers investigated microneedles integrated with pancreatic β-cell capsules which sense the blood glucose levels and secrete the insulin. But the patch was not found to function effectively. Thus microneedle matrix containing synthetic glucose signal amplifiers (GSAs) was developed which was consist of nanovesicles containing glucose oxidaseα- amylase and glucoamylase enzymes. These amplifiers showed the secretion of insulin from the β-cells capsules [65]. The results of clinical study conducted for parathyroid hormone (I-34) coated microneedles demonstrated the 3 times shorter Tmax and 2 times shorter apparent T1/2 compared to conventional injection therapy [66]. These studies indicated that microneedle can be utilized efficiently for the hormonal therapy. Further, these can also be modified for sustained action with the use of suitable polymers [67]. Additionally, iontophoresis in combination with microneedles can also be explored for delivery of various hormones [68].

10.5. Cosmetics

Microneedle use in cosmetics is gaining importance; especially to improve the skin appearance and to treat skin blemishes and scars. An attempt to deliver some cosmetic active ingredients like ascorbic acideflornithineretinyl retinoate was made using the microneedle approach [8]. Melanin was incorporated into phosphatidylcholine liposomes (nanoliposomes) which showed increased solubility in lipids. Amount of pigment that reached deep near the hair structures was found to be more on application by an e-roller [69]. Enhanced delivery of melanostatin, rigin and pal-KTTKS was also investigated through the use of microneedles [70].

10.6. Lidocaine delivery

Lidocaine is used for local anesthesia. Administering lidocaine through microneedle causes less pain as compared to hypodermic injection and thus shows better patient compliance [29].

Baek et al coated the microneedle tips with lidocaine. These microneedles showed consistent in vitro skin penetration and enhanced delivery of the drug in 2 min. Hence, microneedles can be used for pain-free and rapid local anesthesia [36]. In one study, microneedles coated with PEG-lidocaine dispersions showed improved drug delivery within 3 min compared to the topical formulation [1].

10.7. Pain therapy

Meloxicam loaded polymeric microneedles were prepared using polydimethylsiloxane molds. The in-vitro permeation studies showed approx 100% drug release in 60 min. The drug deposition was found to be 63.37% and improved transdermal flux of 1.60 μg/cm2/hr was observed. The permeation increased 2.58 times compared to free drug solution [71]. Neuropathic pain is usually difficult to treat. The available treatments are not able to provide sufficient pain relief and show certain side effects. Dissolvable microneedles were explored for treating neuropathic pain. These delivered selective calcitonin gene-related peptide (CGRP) antagonist peptide and showed high specificity against the receptors. The analgesic microneedle patch showed no skin irritation and side effects. About 75% microneedle dissolved within 20 min on the application [72]. The effective delivery of therapeutics through microneedle has opened the huge opportunities for the industries for pain management.

10.8. Ocular delivery

Many posterior segment indications can be treated by targeting drug delivery. Iontophoresis was used to deliver nanoparticles through the suprachoroidal space. Without iontophoresis, the particles were found to localize at the injection site. When combined with microneedles more than 30% of nanoparticles were delivered to the posterior segment of the eye [73].

10.9. Cancer therapy

Cancer affects many people every year in the world and cancer treatment faces lots of challenges. Microneedles have been investigated for various anticancer drugs delivery. Self-degradable microneedles were investigated for melanoma treatment by delivering anti-PD-1 (aPD1) in a sustained manner. Anti-PD-1 and glucose oxidase loaded pH-sensitive dextran nanoparticles were delivered through microneedle [74]. A topical cream containing 5-fluorouracil is used to treat basal cell carcinoma. The permeability of 5-fluorouracil was enhanced up to 4.5 times when the cream was applied on the skin treated with solid microneedles. Significant inhibition of tumour growth further confirmed improved efficacy using microneedles [75]. Bhatnagar et al investigated the delivery of chemotherapeutic agents- tamoxifen and gemcitabine through microneedles for the treatment of breast cancer. Localized delivery of these drugs would help to reduce the side effects [76]. Polymeric microneedles were also investigated for skin cancer and localized delivery of anticancer drugs [77].

11. Approved products

The first microneedle product was derma roller. Many microneedle products are coming in the market and are approved for medical and cosmetic use [2,29,78]. Some of them are mentioned in Table 4. Many companies in Germany, US, Europe, Japan are selling microneedle products [9].

12. Clinical trials and safety

A lot of pre-clinical studies were carried out on microneedles and were found effective in many aspects but only a few gain successes in human subjects. Kaushik et al conducted the first study for microneedles in human subjects in the year 2001. The aim was to find whether the silicon microneedles are small enough to prevent pain as compared to a 26-gauge hypodermic needle. The microneedles were applied to the forearm of the 12 male and female healthy volunteers selected for the study. The study concluded that the pain caused by the microneedles was less than that caused by the hypodermic needles [79]. Arya and co-workers conducted trials to find whether microneedles cause local skin reactions and acceptable by patients or not. The study was conducted on 15 human subjects. The study demonstrated that the microneedles did not cause any swelling, pain or erythema at the site of application of the patch. The patients were able to self-administer the patches by hand without the need of the applicator. The human subjects preferred these more than the conventional needles [80]. The randomized clinical trial was conducted on 21 men to investigate the enhanced delivery of lidocaine after pretreatment with microneedles. Topical 4% lidocaine cream produced anesthesia after 60 min of the application. With the microneedles pre-treatment, anesthesia was produced within 30 min. [81]. An open trial was conducted on 10 patients for hyaluronic acid-based microneedle patch to investigate the therapeutic effects to treat psoriasis. Calcipotriol-betamethasone ointment was applied on the skin. Microneedle patch was applied over this once every day for a week. The one-week application significantly reduced the psoriatic plaques and thus was found efficient compared to the conventional cream application [82].

13. Current research, challenges, and future trends

The first microneedle was made up of silicon. A study was conducted to explore if microneedle can be used to deliver drugs through the skin more efficiently or not. Initially, the permeation studies were done on cadaver skin to see if large molecules like albumin, insulin can pass through the skin on using microneedles. Further studies confirmed better delivery of large molecules by microneedles. Currently, many new exciting microneedle concepts are coming out which will be of great help in the future [2].

Microneedle approach is being applied to a number of drugs, but it has to encounter various challenges before it can release to the market. A lot of studies have to be conducted to get it clinically approved. The main problems associated with the microneedles technology include, skin allergy, redness and irritation. A limited amount of drug can be loaded into the microneedle. Passing hydrophilic and large compounds through the skin is a major challenge. A proper material has to be selected in the fabrication of these needles, which has adequate mechanical strength and insertion force. The main objective is to increase the permeation without causing pain. It could be difficult for a patient to first poke with a needle and then apply the patch. There is a chance of infection if the skin pores do not close after application [1].

A number of technologies are developing to deliver the drug through the skin. Various modifications have been investigated in the conventional microneedles. 3M’s hollow microneedle is one of them. This emerging technology is flexible enough and can be used to administer some hundreds of milligrams of proteins, which go directly into the systemic circulation [83]. Combination of ultrasound and transdermal drug delivery is also studied in order to further increase the drug permeability [84]. Thus, microneedles can be fabricated with a variety of modifications in order to smartly deliver the drug through the skin providing a new direction and revolution in the field of transdermal drug delivery systems.

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The ‘Current’ Jabs are NOT the ‘Mark of the BEAST.’ HOWEVER, they are ‘NORMALIZING’ Sheeple to be willing and want to get the next or coming ‘vaccine mark’ of authoritarianism IN ‘the forehead or right hand.’ So, should you or should you not get the CURRENT EXPERIMENTAL mRNA ‘genetic affecting vaccines.’ (RNA, DNA, GENES are all inter-linked together.)

Consider the following ‘Common Sense’. I have provided examples of ALL the following in my blogs.

Some people get Covid … don’t die

Some people get Covid … and die

Some people get vaccinated and don’t die

Some people get vaccinated and still die

Some people get vaccinated and still get Covid after being vaccinated

Some people get vaccinated and get very serious side effects (blood clots, aneurysms, paralysis, Covid-Arm, problems with other organs, ‘noisome and grievous sores – blisters – boils.’)

Why are many ‘perfectly healthy’ people dying after getting ANY of the vaccines?

Yes, the vaccine ‘might work’ (or ‘appears to work’) for some and obviously not for others.

98% to 99% percent of People who get ‘Covid’ STILL SURVIVE. THEY DON’T DIE. In other words,

Getting a vaccine is irrelevant for them (and could possibly do them great harm).

There is a ‘genetic link’ as to why some people experience minor symptoms of Covid and others are dead within three (3) days of getting Covid. Just like there is a ‘genetic link’ for just about every other disease known to mankind. A ‘One Size Fits All’ mRNA vaccine is like shooting a shotgun at a flock of ducks a couple of hundred feet overhead. ‘You might kill or hit one or two, but miss or seriously injure the rest.’ Until they invent the ‘next round’ of more enhanced ‘genetically ROBUST modifying’ vaccines (to battle the ‘variants’) that are tailor made for a person or ‘genetically similar people’, these vaccines will ‘miss the mark in some cases, and possibly hit in other cases.’ Unfortunately, NONE OF US knows in which case we might be. Me included.

Do you still want to take an experimental vaccine jab / substance EVEN IF IT IS NOT YET ADMINISTERED INTO YOUR FOREHEAD OR RIGHT HAND????? Since the ‘current’ vaccines are NOT administered IN or UNDER your right hand or IN / UNDER your forehead, they are NOT the MARK.

If you are a healthy person, why ‘RISK’ getting an experimental, genetic modifying substance put into your body that could have MUCH MORE SERIOUS SIDE-EFFECTS THAN WHAT THE VACCINE COMPANIES AND US GOVERNEMENT IS TELLING YOU. Yes, there is a ‘good chance’ you won’t die (tell that to those who DID DIE).  IF there is a 98% to 99% ‘SURVIVAL RATE’ from getting COVID why take an unnecessary risk in dying (or in getting the very serious, life threatening side effects which are NOT A COINCIDENCE).

Since the current ‘jabs’ are not the ‘mark’, this is a discernment for whether or not you should get vaccinated. This is a personal decision between you and God, and should not be ‘forced or coerced’ onto you by any government, police, authorities, media advertising, friend, pastor/priest or religious institutions like the Vatican, Jewish leadership or Muslim Imams. 

The Coming Infrared Biometric Vaccination Mark of the Beast System:

(Five (5); Digital ID, Vaccination Passport, Biometric Infrared Scanning, Vaccine ‘Mark’ or ‘code/number’ of Approval or Authorization, 5G Technology/Network.)

The ‘coming’ mark will most likely involve a ‘subdermal’ (non-hypodermic needle) application of the next wave of vaccinations, that will include a form of ‘digital data memory’ indicating date and time of vaccination. This ‘mark’ of vaccination will involve a sub-dermal outline or image representing a ‘branding’ that can be scanned and revealed by infrared light at a retail checkout point scanner. Just as many people have a physical vaccination ‘mark’ on their arm from getting shots in the 1960s, the coming vaccination mark will be subtle and reside ‘inside’ the human body affecting and indicating a genomic change in the recipient. This is an abomination viewed by God and causes the recipient to lose ‘Imager Status before God’ and results in eternal damnation. The vaccination ‘mark’ has to be easily accessible by scanners and retail checkout points, hence the recipient will have the option of receiving the vaccination ‘patch’ either on their hand or forehead for ‘scannability.’ The patch or medium itself ‘dissolves’ on the exterior of the skin, as the vaccination and information is administered or delivered under the skin. Some technology is currently under development that will possibly allow for the recipient’s health status and response to the vaccine to be ‘scanned’ and ‘verified’ or ‘validated’ at retail or social checkpoints. The purpose of which is to identify whether or not the vaccine has actually worked (and is working) on the recipient’s body / immune system / genetics / RNA / DNA, in addition to informing authorities as to date, time, dosage and manufacturer of said ‘medicine.’

False Prophet (The WORLD’S Greatest Social ‘Influencer’). ‘Go ahead, get the jab, it is good for you, it is good for humanity, it is the ‘moral’ thing to do.’

Revelation 13:16-17 And he [false prophet, pope, pontiff] causeth ALL, both small and great, rich and poor, free and bond, to receive a [‘subdermal, infrared, vaccination, smart’] mark IN their right hand, or IN their foreheads: And that no man might buy or sell, save he that had the [‘subdermal, infrared, vaccination, smart’] mark, or the name of the beast, or the number of his name. (Emphasis mine. Discernment mine.)

Revelation 19:20 

And the beast was taken, and with him the false prophet that wrought miracles before him, with which he [false prophet, pope, pontiff] DECEIVED THEM that had received the [‘subdermal, infrared, vaccination, smart’] mark of the beast, and them that worshipped his image. These both were cast alive into a lake of fire burning with brimstone. (Emphasis mine. Discernment mine.)

Revelation 14:11

And the smoke of their torment ascendeth up for ever and ever: and they have no rest day nor night, who worship the beast and his image, and whosoever receiveth the mark of his name.

Revelation 20:4

And I saw thrones, and they sat upon them, and judgment was given unto them: and I saw the souls of them that were beheaded for the witness of Jesus, and for the word of God, and which had NOT worshipped the beast, neither his image, neither had received his mark upon their foreheads, or in their hands; and they lived and reigned with Christ a thousand years.

5G + Biometric Facial / Hand Scanning + Digital / Cashless Transactions + Mark of Approval / Authorization = Tomorrow’s Economy (2020-2027). Why 2020? Because these ‘things’ have already occurred (past tense) elsewhere (China, India, Asia and a few countries in Europe) in the world in 2020, even though they have not yet occurred in the ‘United’ States.

Biometric scanning used for migrant/border control, secure identity verification and approval, government benefits, domestic and international travel security, economic inclusion of everyone, buying/selling transactions and fund transfers, instantaneous speed of transaction and convenience, VAT/taxation collection, mobility, social credit score and ranking, population movement and tracking, monitoring political and religious ‘extremism’ (terrorists). ‘Mark, number or name’ for verification and approval.

‘Any foreign material(s) should NOT be injected into the human body that causes any kind of change in genetic makeup or structure of a human being. This could be five (5) genetic ‘manipulation’, ‘enhancement’, ‘cutting’, ‘modification’, or ‘alteration.’

Revelation 16:2

And the first went, and poured out his vial upon the earth; and there fell a noisome and grievous sore upon the men which had the mark of the beast, and upon them which worshipped his image. [Symptom or result from having ‘received’ the mark, a result from having changed or damaged a person’s RNA, DNA, Immune System or Genetics].

Both American vaccines use messenger RNA (mRNA) to combat the virus. That is an advanced genetic therapy that uses the virus’ own genetic material against it. Kendrick, however, warns that the technology isreally new and untested, meaning no one really knows how it could affect human health, since it literally hijacks the cellular reproduction mechanism. “We really do not know what these things might end up doing after a prolonged period of time.”

“The plague year of 2020 will be remembered as the time when traditional vaccines were supplanted by something fundamentally new: genetic vaccines, which deliver a gene or piece of genetic code into human cells. The genetic instructions then cause the cells to produce, on their own, safe components of the target virus in order to stimulate the patient’s immune system.”

‘The MARK’ may not be here just yet, but it will be shortly … in terms of a year or two (2023). Verification that a ‘genetic manipulation’ has been administered and will be evident, either in the hand or in the forehead by infrared biometric scanning to enable travel, buying and selling. Do you still ‘want to take’ the jab even if it is not yet administered in your hand or in your forehead in some other manner? If you are curious, please read my other analyses on ‘why’ getting ‘the mark’ is such a bad (understatement) thing in the eyes of God. It is one thing to understand that people in the extremely near future should NOT GET THE MARK. It is another thing to UNDERSTAND WHY THEY SHOULD NOT GET A MARK. This is not a ‘conspiracy theory,’ but the Word of God. I have provided the requisite verses from the Bible, regarding God’s comments about ‘the mark’ of the coming world beast system.

NO ‘MICROCHIP’ NEEDED. Implantable Quantum Dot Microneedle Vaccine INFRARED Delivery System:

MIT researchers have now developed a novel way to record a patient’s vaccination history: storing the data in a pattern of dye, invisible to the naked eye, that is delivered under the skin at the same time as the vaccine. This technology could enable the rapid and anonymous detection of patient vaccination history. The researchers showed that their new dye, which consists of nanocrystals called quantum dots, can remain for at least five (5) years under the skin, where it emits [near-infrared light] that can be detected by a specially equipped smartphone. To create an “on-patient,” decentralized medical record, the researchers developed a new type of copper-based quantum dots, which emit light in the [near-infrared spectrum]. The dots are only about 4 nanometers in diameter, but they are encapsulated in biocompatible microparticles that form spheres about 20 microns in diameter. This encapsulation allows the dye to remain in place, under the skin, after being injected. The researchers designed their dye to be delivered by a microneedle ‘patch’ rather than a traditional syringe and needle. Such patches are now being developed to deliver vaccines for measles, rubella, and other diseases, and the researchers showed that their dye could be easily incorporated into these patches. The microneedles used in this study are made from a mixture of dissolvable sugar and a polymer called PVA, as well as the quantum-dot dye and the vaccine. When the patch is applied to the skin, the microneedles, which are 1.5 millimeters long, partially dissolve, releasing their payload within about two minutes.

By selectively loading microparticles into microneedles, the patches deliver a pattern in the skin that is invisible to the naked eye but can be scanned with a smartphone that has the [infrared] filter removed. The patch can be customized to imprint different patterns that correspond to the type of vaccine delivered. “It’s possible that this ‘invisible’ approach could create new possibilities for data storage, biosensing, and vaccine applications that could improve how medical care is provided, particularly in the developing world,” Langer says.

The quantum-dot patterns could be detected by smartphone cameras after up to five (5) years of simulated sun exposure. The researchers are also working on expanding the amount of data that can be encoded in a single pattern, allowing them to include information such as the date of vaccine administration and the lot number of the vaccine batch. “Storage, access, and control of medical records is an important topic with many possible approaches.” “This study presents a novel approach where the medical record is stored and controlled by the patient within the patient’s skin in a minimally invasive and elegant way.” The research was funded by the Bill and Melinda Gates Foundation and the Koch Institute Support (core) Grant from the National Cancer Institute.

APPLE FACE and PALM ‘INFRARED Photo Detectors’ biometrics planned in 2023 iPhones.

Face ID Infrared biometrics cameras are coming to Apple devices in 2023. A series of patent filings by Apple have hinted at the company’s work on under-display biometric cameras, with the latest published in February (2021).  Apple eyes next-generation biometric scanners for under-display Touch ID. ‘[Infrared photodetectors] could be used for biometric user identification and authentication in the palm or face.’ A new patent application by Apple is signaling the company’s emphasis on biometric ‘photodetector’ technology for under-display touch identification to be potentially deployed on its devices. The sensors include biometric sensors, depth sensors, and cameras. Apple’s listed uses of the photodetectors include security and health monitoring. Arrays of these photodetectors may be deployed to scan fingerprint, palm print, 3D face, or eye biometrics. The [photodetectors could be used for biometric user identification and authentication.] Photodetectors emit electromagnetic radiation against an object such as a finger, face, or stylus. Once reflected by the object, this radiation returns a backscatter which then passes back through the display to register the object’s information. The document also refers to the possibility of using optical, ultrasonic, thermal or other sensing technologies within the system. In addition to this, the photodetectors are also capable of obtaining ophthalmic scans, ECG, and pulse for health monitoring. Other uses of the scanners include palm scanning for social matching and social networking. Apple’s research and development of technology for monitoring health metrics, three patent applications describe [Infrared transceivers] for object recognition. The [infrared transceivers], which may be used in telephones include beam-steering technology and will likely be used for augmented object recognition via visible and [infrared light]. According to the filing, the device can sense objects in a variety of light conditions including visible light, UV, and [infrared spectrum] ranges.

Vaccine INFRARED ‘Micro-Needle SMART Patch’

“Nanocrystals called quantum dots, can remain for at least FIVE (5) years under the skin, forming an ‘image’, where they emit near-[infrared light] that can be detected by a specially equipped smartphone.” (MIT researchers FUNDED by the Bill & Melinda Gates Foundation).

‘Infrared’ Mark of the Beast, 2023 to 2028 = FIVE (5) YEARS.

FIVE (5) is the number denoting Satanic influence over the behavior of evil man’kind (666).

2023 ‘INFRARED’ SMART Phones

2023 ‘INFRARED’ VACCINE MICRO-NEEDLE SMART Patches

Come June, 2021 … 2023 is ONLY 18 (6+6+6) months in the future.

False Prophet

Revelation 13:16-17 And he causeth all, both small and great, rich and poor, free and bond, to [receive a mark IN their right hand, or IN their foreheads]:And that no man might buy or sell, save he that had the mark, or the name of the beast, or the number of his name.

My discernment is that;

2023 / 2024 will mark the ‘roll-out’ of the ‘MARK’ of the BEAST.

2025 will mark the ‘mid-point’ of the 7 Year Tribulation, the Abomination of Desolation revealing the BEAST to be the ANTICHRIST, the Destruction of ‘Mystery Religion’, the beginning of worshipping the BEAST and his IMAGE, and the ‘BEHEADING’ of those who refuse the  Beast’s MARK, refuse to worship the BEAST or his IMAGE. Until 2025, Christians will be ‘protected’ under the MYSTERY RELIGION doctrine of (5) ‘inter-religious dialogue, brotherhood, human fraternity, coexistence and false religious / political peace.’ Upon the enactment of the Antichrist’s Abomination of Desolation and the abolishment of the Mystery Religion, is when BOTH the Jews will become persecuted and have to flee Jerusalem AND Christians will start to be BEHEADED because they will refuse to get the mark and refuse to worship the BEAST and his IMAGE. Beheadings will last during the FINAL 3.5 years of the Tribulation (Great Tribulation) and cease at the end of 2028 / 2029.

God will NOT let Christ’s Bride be Deceived by the Dragon, or his ‘MARK.’

True Church / Bride of Christ Spared from God’s Wrath:

 Romans 5:8-10. “But God commendeth his love toward us, in that, while we were yet sinners, Christ died for us. Much more then, being now justified by his blood, we shall be saved from wrath through him. For if, when we were enemies, we were reconciled to God by the death of his Son, much more, being reconciled, we shall be saved by his life.”

1 Thessalonians 1:10. And to wait for his Son from heaven, whom he raised from the dead, even Jesus, which delivered us from the wrath to come.

1 Thessalonians 5:9. For God hath not appointed us to wrath, but to obtain salvation by our Lord Jesus Christ,

Romans 8:35. Who shall separate us from the love of Christ? shall tribulation, or distress, or persecution, or famine, or nakedness, or peril, or sword?

Jeremiah 30:7. Alas! for that day is great, so that none is like it: it is even the time of Jacob’s trouble, but he shall be saved out of it.

Revelation 3:10 Because thou hast kept the word of my patience, I also will keep thee from the hour of temptation, which shall come upon all the world, to try them that dwell upon the earth.

The ‘mark’ comes shortly, during the tribulation, but the Bride is ‘not here.’ The ‘current’ vaccine(s) are NOT the mark, yet. But they are a ‘precursor’ (‘NORMALIZATION’) of the beast system process, getting people accustomed to getting ‘tagged’, ‘marked’ or ‘branded.’

8 References to ‘BE WATCHING or WATCHFUL.’ ‘8’ indicates that a new ‘era or epoch’ is arriving. Be it the rapture, the tribulation, the year of the Jews redemption or the year of the onset (2028) of the 1000 year millennial reign of Christ (2028-3028).

Matthew 24:42; Watch therefore: for ye know not what hour your Lord doth come.

Matthew 25:13; Watch therefore, for ye know neither the day nor the hour wherein the Son of man cometh.

Mark 13:35; Watch ye therefore: for ye know not when the master of the house cometh, at even, or at midnight, or at the cockcrowing, or in the morning.

Luke 21:36; Watch ye therefore, and pray always, that ye may be accounted worthy to escape all these things that shall come to pass, and to stand before the Son of man

Luke 12:37-39; Blessed are those servants, whom the lord when he cometh shall find watching: verily I say unto you, that he shall gird himself, and make them to sit down to meat, and will come forth and serve them. And if he shall come in the second watch, or come in the third watch, and find them so, blessed are those servants. And this know, that if the goodman of the house had known what hour the thief would come, he would have watched, and not have suffered his house to be broken through.

 ‘Increasing Like Labor Pains.’ ‘Fearful Sights.’ ‘Perilous Times.’ ‘Men’s hearts failing with fear.’ Great Convergence of Signs.’ REDEMPTION IMMINENT.

In His Service,

Night Watchman

Paul Rolland

Night Watchman Ministries

Make Your Decision for Christ NOW!!!!!!! Time is Up!!!!!!!

Jesus Christ’s Offer of Salvation:

The ABCs of Salvation through Jesus Christ (the Lamb)

A. Admit/Acknowledge/Accept that you are sinner. Ask God’s forgiveness and repent of your sins.

. . . “For all have sinned, and come short of the glory of God.” (Romans 3:23).

. . . “As it is written, There is none righteous, no, not one.” (Romans 3:10).

. . . “If we say that we have no sin, we deceive ourselves, and the truth is not in us.” (1 John 1:8).

B. Believe Jesus is Lord. Believe that Jesus Christ is who He claimed to be; that He was both fully God and fully man and that we are saved through His death, burial, and resurrection. Put your trust in Him as your only hope of salvation. Become a son or daughter of God by receiving Christ.

. . . “That whosoever believeth in him should not perish, but have eternal life. For God so loved the world, that he gave his only begotten Son, that whosoever believeth in him should not perish, but have everlasting life. For God sent not his son into the world to condemn the world; but that the world through him might be saved. (John 3:15-17). For whosoever shall call upon the name of the Lord shall be saved.” (Romans 10:13).

C. Call upon His name, Confess with your heart and with your lips that Jesus is your Lord and Savior.

. . . “That if thou shalt confess with thy mouth the Lord Jesus, and shalt believe in thine heart that God hath raised him from the dead, thou shalt be saved. For with the heart man believeth unto righteousness; and with the mouth confession is made unto salvation.” (Romans 10:9-10).

. . . “If we say that we have no sin, we deceive ourselves, and the truth is not in us. If we confess our sins, he is faithful and just to forgive us our sins, and to cleanse us from all unrighteousness. If we say that we have not sinned, we make him a liar, and his word is not in us.” (John 1:8-10).

. . . “And he is the propitiation for our sins: and not for ours only, but also for the sins of the whole world. (John 2:2).

. . . “In this was manifested the love of god toward us, because that God sent his only begotten Son into the world, that we might live through him. And we have seen and do testify that the Father sent the Son to be the Saviour of the world. Whosoever shall confess that Jesus is the Son of God, God dwelleth in him, and he in God.” (1 John 4:9, 14-15).

. . . “But God commendeth his love toward us, in that, while we were yet sinners, Christ died for us. Much more then, being now justified by his blood, we shall be saved from wrath through him. For if, when we were enemies, we were reconciled to God by the death of his Son, much more, being reconciled, we shall be saved by his life.” (Romans 5:8-10).

. . . “For the wages of sin is death; but the gift of God is eternal life through Jesus Christ our Lord.” (Romans 6:23).

. . . “Jesus saith unto them, I am the way, the truth, and the life, no man cometh unto the Father, but by me.” (John 14:6).

. . . “For I am not ashamed of the gospel of Christ: for it is the power of God unto salvation to everyone that believeth.” (Romans 1:16).

. . . “Neither is there salvation in any other: for there is none other name under heaven given among men, whereby we must be saved.” (Acts: 4:12).

. . . “Who will have all men to be saved, and to come unto the knowledge of the truth for there is one God, and one mediator between God and men, the man Christ Jesus.” (1 Timothy 2:4-6).

. . . “For God did not appoint us to suffer wrath but to receive salvation through our Lord Jesus Christ.” (1 Thessalonians 5:9).

. . . “But as many as received him, to them gave the power to become the sons of God, even to them that believe on his name.” (John 1:12).

True Church / Bride of Christ Spared from God’s Wrath:

 Romans 5:8-10. “But God commendeth his love toward us, in that, while we were yet sinners, Christ died for us. Much more then, being now justified by his blood, we shall be saved from wrath through him. For if, when we were enemies, we were reconciled to God by the death of his Son, much more, being reconciled, we shall be saved by his life.”

Romans 12:19. Dearly beloved, avenge not yourselves, but rather give place unto wrath: for it is written, Vengeance is mine; I will repay, saith the Lord.

1 Thessalonians 1:10. And to wait for his Son from heaven, whom he raised from the dead, even Jesus, which delivered us from the wrath to come.

1 Thessalonians 5:9. For God hath not appointed us to wrath, but to obtain salvation by our Lord Jesus Christ,

Romans 8:35. Who shall separate us from the love of Christ? shall tribulation, or distress, or persecution, or famine, or nakedness, or peril, or sword?

Jeremiah 30:7. Alas! for that day is great, so that none is like it: it is even the time of Jacob’s trouble, but he shall be saved out of it.

Revelation 3:10 Because thou hast kept the word of my patience, I also will keep thee from the hour of temptation, which shall come upon all the world, to try them that dwell upon the earth.

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