Status of the document.
This document is a project proposal for the development of starch-based hemostatic products.
Acknowledgement.
Much thanks to the project supervisor who offered guidance in every step of the development of this proposal.
Developing starch based hemostatic products
Project summary.
Purpose: This proposal is envisioned to develop a hemostatic agent from purified plant starch. In this case, the product of the reaction should be developed by the formation of microporous hemosphere particles after etherification, esterification and crosslinking of glucose molecules to form ethyl propanetriol (glycerol-ether links (1-3 deoxy propanol)). The second intention of this study is to investigate the properties exhibited by this product as a hemostatic agent.
Problem statement: The primary research problem in this study is that the natural response of the body does not offer efficient coagulation of blood leading to excessive bleeding in surgical operations or after physical trauma. As a result, hemostatic agents are necessary to enhance the blood coagulation process and reduce the bleeding time. Other hemostatic agents not based on starch have safety concerns because of their association with some heath issues, and as a result, it is necessary to have a well-characterized hemostatic agent whose safety profile is not under any question.
Study Objectives: The core objective of the study is to develop a novel starch based powder for use as a hemostatic agent. Another study objective is to investigate the hemostatic properties of the powder so developed and ultimately characterize the agent. The third objective is to impact human medicine with a highly efficacious hemostatic powder as well as promote research in areas of biomedicine and biopharmaceuticals in order to spur innovation.
Methods and analysis: In this step, the primary reagents and materials include purified starch and epichlorohydrin. In this case, commercial pearl corn starch will be used as the source of starch. The reaction between epichlorohydrin and starch molecules has the end product as ethyl propanetriol. The interaction of molecule of this ester results in cross-linking of a glucose molecule to for a 3D network structure. The resultant material is porous. This characteristic results in increased surface area, which enhances the absorbing capability of the material. After the cross-linking step, a significant improvement of the adhesive properties and shear strength of the starch-based product. Summarily, the development of the MPH in this project will involve three processes of modification of starch, namely etherification, esterification and cross-linking to form a product of molecular weight in the range of 12,000 – 5,000,000 and particle size of 10-1000 microns. The novel starch based material will then be subjected to a series of tests to characterize its hemostatic properties in relation to stability, biocompatibility, and biofunctionality. Besides, the agent will be subjected to safety analysis to establish its safety profile.
Intellectual merit:The intellectual significance this study is that it will develop a novel starch based Microporous Polysaccharide Hemospheres (MPH) with a high shear strength and enhanced adhesive properties for use as a hemostatic agent. This starch based Microporous Polysaccharide Hemospheres will provide an effective hemostatic agent for use in medical and surgical practices in order to avoid costs associated with delayed blood coagulation or excessive blood loss during medical procedures or after physical trauma.
Broader impact: The primary impact of this study will include providing a novel starch based hemostatic agent for use in medical procedures to stop excessive bleeding and promote improvements in the rate of the natural blood coagulation. Sine this this research uses a simplified method of modification of starch to develop high quality Microporous Polysaccharide Hemospheres, there will be the creation of additional commercial value on starch as a biopharmaceutical. An additional impact of this project is that it can impact the fields of emergency medicine, surgery, and chronic disease by providing an effective means of stopping excessive loss of blood during medical interventions. The ultimate impact will be on the public health systems as the product will increase the ability of the medical service providers to have control of important medical procedures involved in the restoration of good health in individual members of the public.
Introduction.
When surgical hemostasis is impractical or inadequate, topical hemostatic agents are used as an alternative/adjunct to the standard suturing techniques in order to ensure wound closure and control bleeding (Peralta, Sanfey and Collins, 2016). Currently over, 50 hemostatic products are available, and each has its strengths, limitations, mode of action and properties (Camp, 2014). The most commonly used agents in the development of homeostatic agents include oxidized regenerated cellulose, gelatin matrix or gelatin sponge and starch powder. By using any of these homeostatic agents, the condition of the patient can improve, and it is also possible to reduce complications as well as direct/indirect costs (Mair, 2011).
Traditional hemostatic methods.
Since the ancient times, practitioners in health services have been searching for effective methods of stopping blood loss by accomplishing satisfactory hemostasis. Some of the earliest ideas in this regard include the application of pressure, bandaging, and application of pieces of clothing and materials on the injured areas. These methods have remained lowly effective, but the discovery of thrombin seemed to turn things around (Camp, 2014). The use of commercially prepared thrombin is one of the products of science and technology that has resulted in the accomplishment of satisfactory hemostasis during surgeries. Other agents that have shown significant efficacies in achieving the same include bone wax, mineral zeolite, which are non-absorbable hemostatic agents but widely applied in clinical practice.
The non-absorbable hemostatic agents named here are associated with inflammations and significant tissue complications (tissue re-burned), which makes them unsuitable candidates. In the last half of the 20th century, significant steps have been accomplished to avoid the problem of non-absorbable hemostatic agents by developing absorbable ones. These agents are generally based on polysaccharides, which are also highly non-toxic, biocompatible, biodegradable, and abundant (Camp, 2014). Among the plant based polysaccharides used for this purpose is starch. It is among the most abundant and cheap polysaccharides, which makes it a good candidate to prepare inexpensive hydrogel as a hemostatic agent. In general, an ideal hemostatic agent should be highly efficacious, easy to use and sterilization, nonantigenic, stable, biodegradable, and inexpensive. It discontinues bleeding by hastening the blood coagulation process, and it is absorbed into the body within a specific period. As an absorbable hemostatic material, starch based hemostatics can make significant contributions to first-aid and rapid hemostasis in the medical industry. Other absorbable hemostatic agents used for the same purpose include microfibrillar collagen, gelatin, oxidized cellulose, fibrin glue, polysaccharides are common agents for absorbable hemostatics. However, these polysaccharides have an animal origin which makes them possible allergens. They are also more costly relative to the plant based polysaccharide hemostatic agents.
The hemostatic market for starch.
Across the globe, the hemostatic market has been expanding every year. In the US, the use of hemostats was popularized during the 1980s and 1990s by surgeons who used them to prevent the threat of disease transmissions and avoid excessive blood transfusions. Originally, these hemostatic products were in the form of gauzes but advancements in technology has paved the way for the use of other agents to obstruct blood outflow in the wound, accelerate clotting reactions and provide a matrix for higher levels of platelet interactions in order to promote faster as well as stronger fibrin clot formation in order to seal vascular injuries (Medimarket Diligence, Inc., 2014).
According to CryoLife, Inc. (2010), as of 2010, the US hemostatic market had an estimated value of $732 million, and that was projected to rise to $1.1 billion in 2014 (CryoLife Inc., 2010). Grandview Research Market Research (2015), estimates the topical hemostat market to increase from about $750,000 million in 2012 to about $1.5 billion in value while that of adhesive/tissue sealants will increase from about $600,000 million in 2012 to about $800,000 million in 2022. The major drivers of the hemostatics industry in the US include high prevalence rate of chronic conditions in the US and the high proportion of American population who are members the geriatric subpopulation. In the US, at least 45 percent of the total population suffers from not less than one chronic condition requiring critical care (Grand View Research, 2015).
The US comprises 36 percent of the global market for hemostatics (Transparency Market Research, 2016). Some of the hemostatic products that rival starch based hemostatic agents include gelatin based topical hemostat, oxidized regenerated cellulose based hemostats (ORCH), collagen based hemostats, active hemostats (thrombin based hemostats), natural tissue sealant, adhesion barrier products, and synthetic tissue sealant (Sudip, 2015).
Use of plant based hemostatic agents.
In the clinical settings, topical hemostatic agents are used in surgery operation and wound management practices. As a result, any medical scenario requiring surgery or wound management necessitate the use of hemostatic agents. According to Wysham, Roque and Soper (2014), topical hemostatic agents can be employed in gynecologic surgery if sutures, electrocautery, and hemoclips fail to meet the primary objective of preventing blood loss. Wysham, Roque and Soper (2014) states that starch powder is one of the hemostatic agents used for that purpose in order to absorb water, and concentrate blood proteins as well as platelets in order to accelerate the formation of clots. (Wysham, Roque and Soper, 2014)
Topical hemostatic agents can also be used to achieve hemostasis in dermatology. Among the most commonly used starch based hemostatic agents for achieving hemostasis in dermatology, according to Glick, Kaur and Siege (2013), is microporous polysaccharide hemospheres (MPH). According to Glick, Kaur and Siege (2013), MPH has been shown to be effective within minutes of treatment. It can be used on open wounds, and in wounds that will be sutured closed (Glick, Kuar and Siege, 2013).
Properties of starch based hemostatic agents.
A suitable powder hemostatic can be described as the one whose application is safe and effective, besides acting synergistically with the chemical as well as hemostatic mechanisms. According to Xi et al. (2014), the Tranexamic acid enhances the hemostatic efficacy of porous starch in order to increase synergism of chemical and physical hemostatic mechanisms (Xi t al., 2014). Another starch based hemostatic is PEG-PPG-PEG copolymer/pregelatinized starch. According to Suwanprateeb et al. (2013), PEG-PPG-PEG copolymer/pregelatinized starch is hard, smooth and consistent and with decreased adherence to the glove. Its clinical usage is also promoted by positive outcomes of cytotoxicity tests in addition to optimized performance (Suwanprateeb et al., 3013).
According to Mirzakhanian, Faghihi, Barati and Momeni (2015), starch based fast-swelling porous superabsorbent hydrogel (FSPSH) hemostatic agent can be prepared by adding acrylic acid plus acrylamide in starch by free-radical polymerization in aqueous solution. When FSPSH adsorbs fluids, it swells and forms a physical barrier that prevents blood loss. Mirzakhanian, Faghihi, Barati and Momeni (2015) also observes that FSPSH is simple to use, stable and harmless, and has a light weight (Mirzakhanian, Faghihi, Barati and Momeni, 2015).
Polysaccharide-based hemostatics.
Oxidized cellulose.
According to Kollar et al. (2008), oxidized cellulose is among the least toxic and the most biocompatible biopolymers. One of the most common sources of oxidized cellulose is wood pulp, which is used to manufacture oxidized regenerated cellulose. When using wood pulp to produce oxidized regenerated cellulose, chemical decomposition is used to refine the product. Oxidized cellulose has several benefits as a hemostatic agent. These benefits include high biosolubility, high biodegradability, good hemostatic effects, wound-healing properties and antioxidant properties. These properties make oxidized cellulose a suitable candidate as a therapeutic agent for different bleeding conditions faced in medical practice. Besides, the therapeutic use of oxidized cellulose in clinical practice is favored by its bactericidal properties towards different aerobic and anaerobic pathogens (Kollar et al., 2008).
According to Zimnitsky, Yurkshtovich and Bychkovsky (2004), mercerized cellulose has more reactivity in the oxidation process compared to the native cellulose, while oxidation of cellulose in the presence of 40% N2O4 leads to increased surface area as well as its swelling in water as a result of destruction of crystallites (Zimnitsky, Yurkshtovich and Bychkovsky, 2004).
Chitosan based hemostatics.
Chitosan is derived from chitin, and it is soluble in acidic aqueous media. According to Pogorielov and Sikora (2015), different brands of chitosan hemostatic agents have different modes of action. However, there are three possible ways of control of bleeding as exhibited by chitosan. One of these modes of action is sorption of plasma, which allows chitosan to be applied as a hemostat. In this case, it absorbs 50-300 percent liquid from the injured part leading to a concentration of erythrocytes and platelets for efficient clotting (Pogorielov and Sikora, 2015).
The second mode of action is erythrocyte coagulation, by cross-linking erythrocytes and facilitating the formation of an artificial clot. The third mode of action is platelet adhesion, aggregation, and activation, which leads to the formation of the natural clot and in the end resulting in the creation of a natural barrier to bleeding (Pogorielov and Sikora, 2015).
Starch-based homeostatic agents.
Starch can be hydrolyzed to glucose by α-amylases which can be found in humans and other mammals. However, the unmodified starch is not suitable to be as a hemostatic agent due to its limitation such as weak, cohesive, rubbery pastes when heated and undesirable gels when cool it down.
This MPH involves a reaction in which the highly purified potato starch solution reacts with epichlorohydrin to form ethyl propanetriol (glycerol-ether links (1-3 deoxy propanol)) which improves the effects of the glucose molecules to crosslink and form a three-dimensional structure into porous and spherical microparticles (Chen et al., 2015; Lewis et al., 2015).
Two of the primary determinants of the application of starch-based homeostatic agents include biocompatibility and bio-functionality. Biocompatibility can be described as the compatibility of materials to biological systems in that they do not elicit local or systemic responses in an organism. A biocompatible material does not have profound effects on the physiological environment. On the other hand, bio-functionality entails the aspect of attaining the biological function after introduction into the body. A biofuunctional material has the properties required for the accomplishment of its intended purposes (Piskin, 1993).
One of the commonly used starch hemostatics is hydroxyethyl starch. According to Kozek-Langenecker et al. (2005), hydroethyl starch solutions are used as plasma expanders in orde stabilize hemodynamic conditions, restore/maintain intravascular volume, as well as improve tissue perfusion, making them appropriate for perioperative situations with characteristically high risk of bleeding. Hydroethyl starch solutions have several impacts on the hemostatic system. For example, when slowly degradable hydroethyl starch solutions is introduced into the body it results in the consistent decrease of the concentration of coagulation factor VIII and von Willebrand factor leading to the impairment of such functional factors as activated partial thromboplastin time or ristocetin cofactor activity. On the other hand, the use of hydroethyl starch solutions has been observed to cause a decrease in the platelet volume. The two negative ramifications of hydroethyl starch solutions, in this case, reduce its efficacy in clinical uses (Kozek-Langenecker, 2005).
According to Goldman and Moulton (2015), purified plant starch provides unique hemostatic properties that can be exploited to develop an implantable device. Goldman and Moulton (2015) adds that purified plant starch has such important properties as being dry and white, fine, sterile, hydrophilic and flowable, which support such hemostatic mechanisms of action as concentration of particulate elements of the blood (blood cells, proteins, and platelets) as well as acting as a strong desiccant. An implantable device developed from starch powder (ARISTA™ AH Hemostat) has been seen to reduce haemostasis, blood loss, and hematoma, and as a result, it has garnered significant recommendations from scientific papers, according to Godman and Moulton (2015).
Another widely known starch powder hemostatic is Starsil® Hemostat, whose primary content is carboxymethyl starch particles. When employed as a hemostatic agent, it forms molecular filters which separate the particulate components of the blood (erythrocytes, proteins, and platelets) from serum. As a result, it absorbs much of the water in the blood, leading to the concentration of blood solids and formation of a temporary mechanical barrier that enhances clotting (Mair, 2011).
Rationale and significance
Hemostats market has been on an upward trend since the 1980s when the medical field embraced their use as primary requirements in invasive surgery management of blood loss. It is estimated that the total market value of hemostatic products across the world will be valued will grow continuously to USD 5.30 billion by 2021 and it will be driven by high demand for hemostatic agents for management/treatment of such conditions as trauma, surgery, myocardial infarction, hemophilia, thrombosis, and stroke. Besides, the high proportion of the US population which comprise the geriatrics will require the further production of hemostatics and for prolonged periods in order to meet their medical needs. There are many sources of materials used in the development of hemostatic products, but animal based carbohydrates and plant based starch form the most important components. For plant based starch, their purification forms the first step of hemostatic development.
This research is designed with the primary urge of developing a starch-based hemostatic product – specifically by using 100 percent plant derived absorbable starch powder. The project also seeks to characterize the product to establish its properties of shear strength and adhesive characteristics (in addition to stability, drug dissolution, and physical-chemical properties) as they will influence the usability of the product as a hemostatic agent.
The priority area of the program is to offer an effective hemostatic agents with a low profile of safety concerns and facilitate the containment of blood coagulation issues witnessed in physical trauma and invasive surgical procedures. During invasive therapeutic procedures or physical trauma, the body is highly susceptible to massive bleeding which may not be controlled through natural body response. As a result, in such situations, it is recommendable to have hemostatic agents to backup the natural blood coagulation system. The natural blood coagulation system cannot stop hemorrhage from large/veins, but a well-designed hemostatic agent can stop such an occurrence within two minutes of application.
In addition, since blood loss is an important factor in the overall recovery from wounds, hemostatic agents are required to be simple to use where even the non-medically trained responders can use to stop bleeding in the case of emergencies. Starch-based hemostatic agents circumvent the problem of complexity as they are not only simple to use but also light and durable. Another problem necessitating the development of starch-based hemostatic agents as sought by this proposal is the expensive nature of direct and indirect costs of bleeding. Starch-based powder hemostatic agents are inexpensive to produce, which could increase their availability and consequently reduce the overall stopping bleeding after trauma or during surgical operations.
In addition, some of the existing hemostatic agents are unsafe for use in some medical situations. For example, WoundStat, a potent procoagulant mineral consisting of smectite granules has been associated with the development of endothelial injury in addition to significant vascular damage. As a result, the agent is unsuitable for use in primary surgical repair. In addition, WoundStat granules, if they enter the systemic circulation, can cause distal thrombosis in the vital organs in the body (Kheirabadi et al., 2010). Since the proposed starch based hemostatic agent is anticipated to have low profiles of safety concern, it will be possible to promote blood coagulation without introducing new health issues in the body. By meeting the requirements of safety and ease of development of the plant based hemostatic, this project promotes sustainability of the healthcare system of the US as it will ultimately reduce the cost of excessive blood loss or those resulting from adverse events of the product.
This study offers to develop a novel hemostatic agent from plant-based carbohydrates/starch by developing a microporous polysaccharide particles with enhanced adhessive properties and high shear strength, and as a result increasing the usability of starch as a high-value hemostatic agent. Through investigations carried out this study, there will be a full characterization of the Microporous polysaccharide particles so developed in orde to spell their hemostatic properties with regard to stability, biocompatibility, biofunctionality, and physical-chemical properties. Other areas of importance that will be affected by this project include pharmaceutical and biomedical sciences as it will set the stage for further investigations of the novel agents for other applications apart from hemostatics. By promoting further researches, this area of study will promote innovation and thus promote the universal goal of innovation in such fields as biopharmaceuticals and human medicine.
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