Diabetes is a disease in which your blood sugar is too high, blood glucose is the human body's primary source of energy and when it’s too high many complications arise and must be addressed. Although standard oral insulin delivery is a safe direction to follow, sometimes severe complications may arise. Fortunately, nanotechnology could surmount many of the hurdles that come with standard insulin delivery. In this article, we discuss the current and promising applications of nanotechnology in treating diabetes, as well as, the advantages and limitations of using them. We explore enhancing insulin delivery using nanotechnology, incorporating nanotechnology into imaging to improve the effectiveness of islet cell transplants, and even treating chronic wounds.
Ayman Abdulhameed Mohammed, Grade 12, Harmony Science Academy - Euless, TX
#Research #Nanotechnology #AymanAbdulhameedMohammed #InsulinDelivery #DiabetesTreatment #DiabeticFootUlcers #TheranosticImaging
Abstract:
Diabetes is a disease in which your blood sugar is too high, blood glucose is the human body's main source of energy and when it’s too high many complications arise and must be addressed. Although the standard oral insulin delivery is a safe direction to follow, sometimes severe complications may arise with it. Fortunately, nanotechnology could surmount many of the hurdles that come with standard insulin delivery. In this article, we discuss the current and promising applications of nanotechnology in treating diabetes, as well as, advantages and limitations of using them. We explore enhancing insulin delivery using nanotechnology, incorporating nanotechnology into imaging to improve the effectiveness of islet cell transplants, and even treating chronic wounds.
Introduction
Diabetes is the ninth leading cause of death worldwide, contributing 11.3% of deaths globally. According to the world health organization, the number of people who have diabetes has quadrupled since 1980 [Saedi et al, 2019, Results]. About 1.5 million Americans are diagnosed with diabetes every year. If something is not done to slow down the increasing rate of people diagnosed with diabetes, then it is expected by 2050 that one in every three Americans will have diabetes[Roglic, 2016, Mortality].
Diabetes is a chronic condition in which the body produces insufficient insulin or fails to use it properly. Insulin, a hormone produced in the pancreas, is needed to convert sugar, carbohydrates, and other nutrients into energy to function daily. Unfortunately, the conventional method of administering insulin (oral or pulmonary) is not only inconvenient but also has many drawbacks, such as psychological stress or peripheral hyperinsulinemia [Li et al., 2013, Introduction]. Fortunately, nanotechnology has made it possible to create gadgets on an atomic, molecular, and even super molecular level. The application of nanotechnology in medicine has enabled us to cure diseases at a lower cost, quicker rate, smaller size, and less energy-intensive pace [Iman et. al, 2014, pg.3]. With diabetes being one of the top causes of mortality globally, scientists have recently brought nanotechnology to diabetic therapy. With the implementation of nanotechnology, these systems can now treat diabetes more safely and efficiently[Yannis et al., 2021, “Nanotechnology in medicine”]
Current and promising applications of nanotechnology include drug delivery, imaging nanoprobes, therapeutic nanomaterials, biocompatible nanomaterials, and even diabetic wound healing. Many of these opportunities have already become realities and are even being used today, while others have shown strong promise in the early stages of their development.
Insulin Delivery
Using nanoparticles as insulin carriers have been extensively explored in recent years. The term nanoparticle can be split into two different categories, nanospheres and nanocapsules; their morphological structure distinguishes both, and both have their respective ways of carrying drugs.
Both types of nanoparticles have unique characteristics, and drug release techniques are Nanospheres are a matrix system[Subramani et al, 2012]; when released, the drug disperses in a uniform fashion that dissolves insulin inside their oily core and surrounds it with a shell that can control the release of the drug from the core. On the other hand, nanocapsules are vesicular systems that retain the drug inside a unique membrane. Both types of nanoparticles can be used for unique purposes and have distinct qualities that make them valuable in delivering insulin.
In recent years, nanotechnology has been explored as an alternative to insulin delivery because of its ability to control the release of insulin, its efficiency, and the potential to improve the lives of people with diabetes dramatically. After delivering insulin into the body, the nanoparticle dissolves into a biologically acceptable compound such as lactic and glycolic acids, which are Biocompatible materials approved by the Food and Drug Administration (Kreb's cycle) [Pandita et al., 2014]. There are various types of nanotechnology, polymeric, ceramic, and even gold. Each has its advantages and limitations that make them useful for particular uses, as shown in.
Polymeric Nanoparticles
Polymeric NPs have been a primary candidate in employing nanoparticles as drug carriers due to their size (1-100 nm) and potential for the controlled release of insulin. In addition, these particles can degrade into biologically acceptable materials by hydrolysis, as well as provide lesser cytotoxicity, higher target specificity, more insulin containment, and most importantly, the ability to preserve the insulin, bypassing all external elements in the stomach[Mansoor et al., 2019]. There are many approaches regarding polymeric nanosystems. The primary and current approach is enhancing the traditional oral administration of insulin by merging polymer nanotechnology. First, the drug (insulin) will be trapped inside the polymer membrane; encapsulating the insulin within a strong membrane will protect the drug through the stomach to maximize delivery[Subramani et al., 2011]. Once the system reaches its desired destination, the erosion process begins; the outer layer is created out of a polymer material that will disintegrate into a biologically acceptable compound (In water lactic or glycolic acid degrade into biologically acceptable compounds) after the erosion process is complete the drug (depending on the type of nanoparticle utilized) will disperse.
Another approach is self-contained polymeric insulin delivery. These are biodegradable systems that contain a polymer-inulin matrix encapsulated inside a nanoporous membrane with a grafted glucose oxidase[Subramani et al, 2011]. The nanoporous membrane can recognize a drop in blood glucose levels and trigger the rest of the membrane, beginning the biodegradation process and ultimately releasing the insulin. Furthermore, the glucose oxidation reaction results in a rise in the pH levels within the membrane environment; this causes the system to swell up, which results in an increased amount of insulin delivered. This molecular gate system is composed of a copolymer. At normal pH levels, the polymer swells up in size and closes the "gate" to prevent any disturbances to the insulin. When blood glucose levels are higher, and pH levels increase, the gates "open" and release insulin from the central matrix.
In the past, the main focus of research regarding polymeric nanotechnology was identifying naturally occurring biocompatible polymers. Polymers such as cellulose and collagen are good examples of this. However, recent research has shifted from naturally occurring polymers to chemically synthesizing biodegradable polymers, enhancing their characteristics[Song et al., 2018]. Some examples are polyanhydrides, polyacrylic acids, polyurethanes, and even polyesters[Panchal et al., 2020].
Although current research is mainly aimed toward oral insulin delivery, the prospect of polymer-based nanotechnology insulin delivery systems holds so much promise for the future of diabetic treatment. Therefore, it is crucial that any type of treatment system used in insulin delivery is biocompatible. Furthermore, they should be assessed thoroughly for safe and effective application with minimal side effects.
Ceramic Nanoparticles
Another recently brought up system is ceramic nanoparticles, like polymeric nanoparticles with higher biocompatibility and an ultra-low size. The systems are mostly made of calcium phosphate, silica, aluminum, or even titanium [Subramani, 2011]. These systems have unique advantages such as straightforward synthesis, high biocompatibility, and miniature size. They also protect drugs from denaturation caused by external changes like pH and body temperature. Furthermore, their surfaces can be modified with a variety of moieties in order to target a specific location. Calcium Phosphate systems were studied and tested in vivo to determine if it is a better insulin delivery substitute [Corkery, 2000]. Results showed that the systems were more effective in delivering insulin when compared to the standard porcine insulin solution. Unlike polymeric nanoparticles, these systems have the potential to be manufactured to a specific size; because of this, the idea of inhalable ceramic nanoparticles has recently been researched.
The inhalable drug system must be small enough to avoid clogging the lungs and large enough to prevent exhaling; this allows the direct delivery of insulin into the bloodstream without the patient experiencing pain through an injection. In 2001, a study tested this theory using PLGA (poly lactic-co-glycolic) nanospheres in guinea pigs' lungs and found a significant reduction in blood glucose levels after 48 hours compared with the insulin solution [Paul W et al, 2008]. Unfortunately, many factors limit the bioavailability of insulin's nasal administration, such as poor permeability and a rapid mucociliary clearance mechanism that removes the non-mucoadhesive formulations from the absorption site. To surmount these constraints, mucoadhesive NPs based on starch and chitosan have been introduced. Results showed they maintained good insulin capacity, releasing 75-80% of insulin within 15 minutes [Subramani et al., 2011].
Gold Nanoparticles
Gold has been an effective metal in medicinal and therapeutic applications. Gold nanoparticles have shown promise in being used as insulin carriers and have been investigated frequently in the last decade primarily due to their biocompatibility, stability, simple synthesis, and inexpensive preparation. They have proven their long-term stability along with a solid 53%. One study concluded that chitosan-reduced gold nanoparticles enhanced insulin delivery and improved insulin's pharmacodynamic activity [Bhumkar et al., 2007]. The chitosan is used for two purposes, acting as a reducing agent between the creation of gold nanoparticles and enhancing insulin penetration and absorption of the oral and nasal mucosa. Another study that treated diabetic mice with gold nanoparticles found that following the treatment, the rats experienced a reduced level of glucose caused by ROS generation (a critical factor in the growth of diabetic complications)[Barathmanikanth et al., 2010]. However, widespread distribution in crucial organs such as the kidney and liver limits their true potential. Because of their potential toxicity, gold nanoparticles must be thoroughly characterized before their application to guarantee it is a safe application. However, more studies must be conducted to find the optimal size dosage to maximize their practical use.
Nanotechnology Theranostic Imaging
Theranostics, a combination of diagnosis and therapy inside of one nanoplatforms, is, in itself, remarkable. Because of their unique roles as delivery agents, nanoparticles are used as capsules to carry therapeutics into target locations during imaging [O’Dorisio, 2018]. Many therapeutic approaches, including chemotherapy, radiation therapy, and even immunotherapy, have been researched to integrate theranostic nanoplatforms.
Recent advances in nanotechnology have provided a new perspective to theranostic imaging. Nanoparticles allow for simultaneous diagnosis and therapy, and possess the ability to deliver various drug prospects that, unfortunately, are put aside due to solubility or similar reasons. One example of this is Superparamagnetic Iron-Oxide (SPIO) nanoparticles used for theranostic imaging [Wang et al., 2014]. These are generally composed of three main characteristics, A superparamagnetic iron core that is biodegradable, A multi-functional polymer surface that not only serves as a protective layer but also as a functional layer equipped with multiple linkers, and finally, various components with diverse applications attached to the coating. This type of nanoparticle helps locate and traffic the therapeutics moieties.
Incorporating Islet Transplantation & Theranostic Imaging
One of the most promising therapeutic approaches for type 1 diabetes treatment in the last decade or so is islet transplantation. The Edmonton protocol (clinical islet transplantation) improves the success rate of isle transplantation, with an 80% insulin independence after one year [Agarawal et al., 2012]. However, this rate significantly decreases after five years due to islet graft loss after transplantation. Allogeneic immune response, recurrence of auto-immunity, and nonspecific inflammation are reasons islet graft loss occurs following these transplantations [Wang et al., 2014]. One way to overcome this is Theranostic MRI; with the combination of tracking transplanted islets for the detection of islet graft loss, and the ability to provide graft protection, theranostic imaging is a profitable way to overcome these complex challenges.
Theranostic MRI To Treat Islet-Graft loss
One approach to treating islet-graft loss using theranostic MRI is graft encapsulation. Barnett et al. developed SPIO-labeled alginate magneto capsules with a desire to monitor and protect transplanted islet cells from graft loss [Barnett et al., 2007]. The magneto capsules were successfully able to restore normoglycemia in STZinduced diabetic mice and diabetic swine transplanted with human islet cells. Furthermore, the MRI was able to monitor the distribution and localization of the transplanted islets over time in vivo in real-time. Afterwards, Burnett et al. incorporated perfluorocarbon emulsions into alginate microcapsules containing insulin to determine whether alginate microcapsules along with PFCs increased insulin secretion while simultaneously enabling multimodality imaging. Results showed that after the placement of immune protected insulin encapsulated cells in mice, a strong insulin level was achieved with human c-peptide levels and the fluro capsules performed with MRI, USI, and CT with sound research and clinical grades for all modalities.In essence, PFC capsules increased insulin secretion of encapsulated islet cells by 18.5% compared with non fluorinated alginate microcapsules after 7 days. This study represents the significance of theranostic capabilities in immunoprotection islets and tracking islets safely and efficiently.
Future of theranostic imaging
Although research regarding theranostic imaging has just beagan, theranostic imaging holds a promising future for T1D treatment. In such a short amount of time, the progress that has been made shows encouraging new developments for clinical application. Theranostic imaging has the potential to revolutionize both drug delivery and imaging altogether, and could change modern medicine for the better.
Diabetic foot ulcers
One of the most common complications of patients who have diabetes and do not comply are diabetic foot ulcers. Diabetic foot ulcers are usually caused by poor glycemic control, underlying neuropathy, peripheral vascular disease, and poor foot care. Diabetic foot ulcers are usually painless due to the loss of sensation in the feet. They are the leading cause of non-traumatic amputations in the US with 5% of diabetic patients developing a foot ulcer, and 1% are amputated [Oliver et al., 2022]. Current treatments include protecting the ulcer from exterior infection, dead tissue removal, and absorbing excess fluid. Nanotechnology has developed interest in this area due to their unique characteristics.
Using Nanotechnology to treat diabetic foot ulcers
Nanotechnology has a unique trait that allows it to deliver molecules like DNA, RNA, and GF's, making it a promising candidate for treating chronic wound healing. In addition, nanotechnology's small size and biocompatibility allow for an enhanced intracellular treatment while protecting and preserving the biomolecules and drugs from degradation and speeding up time, and lowering application. Furthermore, the different release profiles of treatment within the carrier can be matched to the wounds healing requirements.
Metallic NPs for DFU treatment
Metallic NP's have intrinsic properties that make it suitable for treating chronic wounds. Gold, copper oxide, iron oxide, and even titanium dioxide are some examples of metals with antibacterial properties. Along with RNA, DNA, and enzymes, these metals provoke bacterial death which is why nanotechnology is a good candidate to treat chronic wounds. Nanofibers encourage wound healing because they provide a high surface area to volume ratio, tunable mechanical properties, increased mechanical porosity, and their ability to encapsulate biocompounds and drugs. These traits allow the cells to interact with the matrix during functionalization and restoration.
Silver NPs for DFU treatment
Silver nanoparticles, due to their antimicrobial, anti-inflammatory, and wound healing properties are one of the most used nanoparticles in wound healing. Its inclusion in various formulations to control ion release is crucial due to the toxicity resulting from the silver ions release. Silver Np's have been incorporated in gels such as PEG-chitosan, polyacrylic acid, and foams, which have proven to be effective at treating diabetic wounds and reducing the metal's toxicity. One study, conducted by Shi et. al created hydrogels consisting of maleic acid-grafted dextran and thiolated chitosan encapsulated inside silver nanoparticles. The hydrogels had displayed adequate self-healing properties, repeatable adhesiveness, anit-bacterial activity.Wound healing was also promoted through, reduced inflammation, increased angiogenesis, and increased collagen deposition.
Gold NPs for DFU Treatment
Gold Nanoparticles have also recently been explored as potential candidates for diabetic wound healing. Gold Nanoparticles have been included with antioxidant biomolecules to increase the effects of its wound healing properties. A study conducted by Martinez et al. constructed a gold nanocomposite combined with chitosan and calreticulin, which is a calcium binding protein of the endoplasmic reticulum that has shown wound healing properties. Results confirmed that it did improve healing after being administered into diabetic mice.
Lipid NPS for DFU Treatment
Lipid nanoparticles are naturally prepared without physiological lipids or lipid molecules in processes that do not require the introduction of any toxic natural solvents. For wound healing applications, lipid Np's are generally loaded with specific siRNAs. A study conducted by Motawea et al. modified the preparation of a LNP to achieve better entrapment and sustained release on treating diabetic foot ulcer treatment. The results displayed that foot ulcers treated by the phenytoin-NLC hydrogel had smaller area when compared with the blank PHT hydrogels.
Silicon Ions
Silicon ions have also been used to treat diabetic wounds, Jiang et al. prepared a space oriented scaffold for Si ion release. The scaffolds were coated with Silicon doped amorphous calcium phosphate nanoparticles coating its surface to encourage angiogenesis, collage disposition, and the re-epithelialization of the diabetic wound. The modified NPs loaded with flightless 1 neutralizing antibodies showed a significant improvement in healing compared to controls and the antibody alone in diabetic wounds.
Limitations of nanotechnology application of diabetic wounds healing
Even though these metallic nanosystems have antibacterial properties, therapies are limited because high levels of metals in the body destroy human cells. However, there are many solutions to this, one example of a solution is modifying the surface of a particle, by modifying the surface, we can limit the toxic effects and stabilize the entire carrier. Another method would be synthesizing metals to limit toxic properties and enhance their output. Both solutions would reduce the metal's toxicity while preserving their antibacterial properties.
Future Perspective of DFU Treatment Using Nanotechnology
Diabetic wound treatment using nanotechnology incorporated with siRNAs is an exciting prospect to wound treatment and has significant potential as a wound healing treatment. Because of their biocompatible nature and ability to deliver drugs at a supramolecular level, nanoparticle drug delivery to treat DFU is an effective form of treatment. Research has been conducted to intensify the efficiency and specificity while lessening side effects as much as possible. Furthermore, when compared with the traditional antibiotic treatment of DFU, nanoparticles have displayed that they are more effective at administering treatment to eradicate bacteria developing resistance. Current research on nanoparticle treatment for DFU is increasing at an exponential rate and will undoubtedly have a positive impact on diabetic patient's quality of life. Hopefully, nanotechnology will be the next frontier in meeting clinical needs to heal chronic wounds.
Conclusion
Research regarding nanotechnology has exponentially developed into a revolutionary form of diabetic treatment in a short amount of time. Additionally, nanotechnology has expanded to many other diseases as a successful therapy. In cancer, for example, a pegylated liposome loaded with a chemotherapy agent was the first nanoparticle-based therapy approved by the FDA in 1995. Since then, nanotechnology has had substantial progress as a cancer treatment. Nanotechnology has so much untapped potential that could revolutionize the world of modern medicine.
Significant developments in self-contained insulin delivery as well as inhalable insulin, have been led by nanotechnology. Self-contained insulin delivery systems work as a gate system in which the gate systems and can recognize a drop in blood glucose levels by measuring pH levels, when pH levels increase the system releases insulin and when the system is at normal pH levels the system swells up to "close" the gate and preserve insulin within the matrix. Inhalable insulin has also significantly improved in the past decade and is getting closer to clinical application.The inhalable insulin is created using ceramic nanoparticles, unique to their ultra-low size. The ultra low-size allows the particle to be large enough to be inhaled but not small enough to be exhaled, once they are inhaled they follow the same process as a standard insulin carrier, reaching the area of low glucose levels and then degrading in biocompatible material to release the insulin inside the matrix. Nanotechnology has also provided a new perspective to imaging as well in theranostic imaging, a combination of therapy and diagnostics, theranostic imaging is used to diagnose and treat diseases altogether.
Furthermore, theranostic imaging can be used for islet transplantation (Edmonton protocol), and has proven to make the possess more efficient. Therefore, theranostic imaging by itself and incorporated with islet transplantation holds a promising future for T1D treatment. A common complication of diabetic patients with poor glycemic control is diabetic foot ulcers, which are large wounds at the bottom or near the foot. Fortunately, nanotechnology with the combinations of its unique drug delivery trait and its antibacterial properties make it an excellent candidate to treat diabetic wounds. Furthermore, nanotechnology can deliver and preserve mRNAs, siRNAs, and other molecules to effectively treat the wound safely.
Major Limitations concerning nanotechnology should be addressed as the scientific community isn’t completely sure on how the natural human body would react to nanotechnology. In comparison to their volume nanoparticles have large surface area. Friction and clumping may affect their use as drug delivery agents. Their miniature size allows them to be excreted however, when they clump together they can gather in crucial organs and cause organ failure due to toxicity.
However, even though there are limitations, with the current rate of research and advancements in nanotechnology, it is inevitable that a solution will be found, All of these nanotech applications have unique characteristics that not only make the patient life for diabetic patients easier but also relieve diabetics complications from traditional diabetic treatment. The materials are the leading edge of a rapidly developing industry-changing how we think of modern medicine. Currently, most commercial applications of nanotechnology have to do with drug delivery, however, with the rapid development of nanotechnology, hopefully, we see a wide variety of uses to treat not only diabetes but also other diseases.
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