Chitosan hydrogel microneedle patch device with myocardial stem cell packaging and transferring functions

Abstract

The invention discloses a chitosan hydrogel microneedle patch device with myocardial stem cell packaging and transferring functions, and relates to the technical field of stem cell transferring microneedles. Comprising a cell dissolving pool and hollow microneedles arranged in an array; the cell dissolving pool is composed of a base plate and a surrounding plate, the surrounding plate is vertically arranged to form a circle, the base plate is arranged at the bottom of the surrounding plate and connected to the bottom of the surrounding plate, and a cavity formed by the base plate and the surrounding plate is used for conducting closed packaging on stem cells; the hollow microneedles arranged in an array are arranged at the outer bottom of the cell dissolving pool, the roots of the hollow microneedles are connected to the substrate, and anti-skid lines are distributed on the substrate. The microenvironment of the myocardial infarction position can be effectively improved, the retention rate and the survival rate of stem cells in myocardial tissue are increased, and the stem cells are conveyed into myocardium as many as possible.

Description

Technical Field

[0001] The present invention belongs to the technical field of stem cell transport microneedles, and more specifically, to a chitosan hydrogel microneedle patch device with the function of encapsulating and transporting myocardial stem cells, and belongs to the technical field of medical auxiliary equipment. Background Art

[0002] Myocardial infarction is one of the leading causes of death and disability worldwide. It is a serious acute coronary heart disease caused by coronary artery blockage, characterized by myocardial ischemia and necrosis leading to myocardial function damage. Myocardial infarction is one of the main causes of death from heart disease. It is an acute and severe disease with a high mortality rate, which seriously threatens people's life and health.

[0003] Stem cells are primitive cells with the potential for self-renewal and differentiation, which can become different types of cells through directed differentiation. This means that stem cells can undergo multiple cell divisions and differentiations and maintain the ability to differentiate. The directed differentiation function of stem cells allows them to become precursor cells of any type of cell, such as cardiomyocytes, nerve cells, stem cells, etc.

[0004] Many clinical trials aim to transplant stem cells into the heart to protect or alleviate the patient's myocardial infarction symptoms. The self-repair ability of myocardial cells after myocardial infarction is extremely limited. At this time, the heart cannot effectively transport blood to the whole body. As the blood supply to the myocardium decreases, the lack of oxygen and nutrients in the myocardial cells will quickly lead to cell death. It can only be treated with lifelong drug-assisted treatment or even by implanting mechanical assist devices. At present, although some effective methods for treating myocardial infarction have been reported, such as intramyocardial injection, the cell retention rate is always low. By consulting relevant literature and comparing relevant experimental data, the best method at present is to deliver cells to the myocardium through a combination of patches and microneedles to repair areas of myocardial necrosis.

[0005] Microneedles are arrays of tiny needles of different shapes and heights that deliver drugs in a minimally invasive manner, thereby achieving painless drug administration. Microneedle technology is an auxiliary technology for the treatment of cardiovascular diseases with broad application prospects. Through the implantation of microneedle patches, the site of cardiac lesions can be repaired, the fit and biocompatibility of the myocardium can be improved, and the speed at which the site of cardiac lesions returns to normal heart function can be accelerated. Microneedle technology can not only release drugs directly into the diseased tissue and maximize the effect of the drug on the affected area, but also the time and dosage of auxiliary treatment can be precisely controlled, thereby avoiding unnecessary side effects and adverse reactions, greatly improving the efficacy. This is of great value for the auxiliary treatment of cardiovascular diseases such as myocardial infarction and heart failure.

[0006] Currently, commonly used methods of delivering stem cells include coronary artery injection, intravenous injection, and intramyocardial injection. Intracoronary artery injection is prone to cause microvascular embolism, while intravenous injection does not specifically target damaged heart tissue, but distributes throughout the body. Intramyocardial injection is a delivery route for stem cells to directly enter myocardial tissue, which can deliver stem cells to remote areas or ischemic and hypoxic infarction areas. It is difficult to bring them to the designated area of ​​stem cells, which makes the retention rate and survival rate of stem cells low, reducing the effect of auxiliary treatment. Summary of the invention

[0007] One of the technical purposes of the present invention is to improve the retention rate and survival rate of stem cells in myocardial tissue and to deliver as many myocardial stem cells as possible to the inside of the myocardium. The chitosan hydrogel microneedle patch device structurally adopts a hollow microneedle structure consisting of a main needle and four auxiliary needles with a certain inclination angle. Through this structure, the microneedle patch device can be tightly attached to the surface of the myocardium during the entire myocardial stem cell delivery process, ensuring that the internal myocardial stem cells can fully enter the myocardium and be accurately and stably delivered. Based on the positioning and fixation of the main needle and the auxiliary fastening connection of the auxiliary needle, the chitosan hydrogel microneedle patch device is fixed to the surface of the myocardium, providing a stable connection for subsequent myocardial stem cell delivery.

[0008] The second technical purpose of the present invention is to use chitosan to make hollow microneedles to form a gradual dissolution channel, which is more conducive to the delivery of myocardial stem cells. Chitosan is easily soluble in water and can be metabolized and absorbed by the human body. The chitosan hollow microneedles will gradually dissolve, and more and larger channels will be formed at this time, allowing myocardial stem cells to enter the myocardium autonomously, accelerating the transport speed. Subsequently, the substrate made of chitosan will also gradually dissolve, and the transport efficiency will reach the maximum at this time; through this gradual dissolution channel design, the release of myocardial stem cells is continuous and gradual, ensuring the stability and efficiency of delivery.

[0009] The third technical purpose of the present invention is to improve the myocardial stem cell delivery rate and reduce the adhesion rate of myocardial stem cells. In order to make myocardial stem cells adhere less to the inner wall base of the device and ensure that myocardial stem cells enter the myocardium as much as possible, the inner wall base of the microneedle patch device adopts arc chamfer transition, the bottom surface is not a flat bottom surface, but slightly concave downward, and the outer bottom of the microneedle patch device adopts a step chamfer transition. The two ingenious designs cooperate with each other to achieve a faster delivery rate and a lower myocardial stem cell adhesion rate. The cell lysis pool adopts a closed structure and a certain pressure is preset inside. When the chitosan hydrogel microneedle patch device is fixed on the myocardial surface, myocardial stem cells and cell fluid are transported to the inside of the myocardium based on the internal preset pressure; the concave structure design adopted at the bottom of the microneedle patch device is more conducive to the release of the internal preset pressure. The concave and outer bottom step chamfer transition design of the microneedle patch device is combined with the internal preset pressure of the closed structure to optimize the mechanical driving performance of the chitosan hydrogel microneedle patch device and meet the needs of surgery.

[0010] The fourth technical purpose of the present invention is to ensure that the microneedle device is tightly adsorbed on the surface of the myocardium. An anti-slip pattern with a certain depth is set on the supporting substrate to increase the friction between the supporting substrate and the myocardial surface; hydrogel is used to wrap myocardial stem cells. The hydrogel has good encapsulation biological cell activity, and its degradation products are non-toxic amino acids, etc.

[0011] The fifth technical purpose of the present invention is to provide an operation method of a hydrogel microneedle patch device with the function of transporting myocardial stem cells. Based on the structural characteristics, mechanical properties and functional characteristics of the hydrogel microneedle patch device with the function of transporting myocardial stem cells, the targeted delivery of myocardial stem cells is achieved and the delivery efficiency is guaranteed under the premise of safe and stable transportation.

[0012] In order to solve the above technical problems, the technical solution adopted by the present invention is: a chitosan hydrogel microneedle patch device with the function of encapsulating and transporting myocardial stem cells, the chitosan hydrogel microneedle patch device with the function of encapsulating and transporting myocardial stem cells is applied to the surface of the myocardium, comprising:

[0013] The cell lysis pool is composed of a base plate and a surrounding plate, the surrounding plates are erected to form a circle, the base plate is arranged at the bottom of the surrounding plates, the base plate is connected to the top of the surrounding plates and closes and packages the myocardial stem cells and nutrients in the cavity formed by the base plate and the surrounding plates; the interior of the closed package has a certain preset pressure;

[0014] The arrayed hollow microneedles consist of a main needle and four auxiliary needles, which are arranged at the outer bottom of the cell lysis pool, and the roots are connected to the substrate. The hollow microneedles and the substrate are made of chitosan. The enclosure is made of hydrogel.

[0015] The substrate, the surrounding plate and the hollow microneedles are integrally formed.

[0016] Preferably, the hollow microneedle is a shell-like porous structure made of chitosan. As time goes by, the chitosan hollow microneedle will gradually melt to form a larger channel, thereby increasing the speed at which myocardial stem cells enter the myocardium. The substrate is a plate-like porous structure made of chitosan. The enclosure is composed of a hydrogel with a thickness of 500 to 1000 μm. The cell lysis pool is coated with myocardial stem cells and nutrients required for the survival of myocardial stem cells, which can improve the microenvironment of myocardial infarction and promote the transplantation and survival of myocardial stem cells in the heart.

[0017] Preferably, the hollow microneedle is conical, triangular pyramidal or quadrangular pyramidal, with a height of 0.5-4 mm, a needle tip diameter of 50-100 μm, a needle body bottom size of 200-500 μm, a shell wall thickness of 500-800 μm, and a hole diameter of 20-50 μm on the shell side wall.

[0018] Preferably, the thickness of the substrate is 300-500 μm, the thickness of the surrounding plate is 500-1000 μm, and the center distance between two hollow microneedles is 600 μm.

[0019] An operating method of a hydrogel microneedle patch device having the function of transporting myocardial stem cells comprises the following steps:

[0020] First, myocardial stem cells and nutrients that maintain the survival of myocardial stem cells are placed in the cell lysis pool. At this time, the substrate is in an open state.

[0021] Second, myocardial stem cell encapsulation is performed by bonding the substrate and the surrounding plate to complete the myocardial stem cell encapsulation and obtain an encapsulated chitosan hydrogel microneedle device;

[0022] Third, the encapsulated chitosan hydrogel microneedle device is placed in saline for storage. When the device is needed, it is directly taken out of the saline; one side of the microneedle is pressed against the surface of the myocardium. The hollow chitosan microneedle has sufficient hardness to pierce the myocardial epithelial cells, forming a channel for myocardial stem cells to pass through. At this time, myocardial stem cells enter the myocardium from the through hole of the substrate through the hole of the hollow chitosan microneedle; as time goes by, the hollow chitosan microneedle and the substrate gradually melt, which speeds up the entry of myocardial stem cells into the myocardium.

[0023] Finally, when all the myocardial stem cells are delivered into the body, the entire chitosan hydrogel microneedle patch will be broken down into macromolecules inside the body and metabolized and excreted.

[0024] The beneficial effects of adopting the above technical solution are:

[0025] (1) The present invention has a novel structure and applies microneedle technology to the field of auxiliary treatment of heart diseases. In particular, a chitosan hydrogel microneedle device is prepared, which can transport myocardial stem cells and effectively deliver stem cells to a designated location of the myocardium to achieve the purpose of auxiliary treatment of myocardial infarction;

[0026] (2) The device of the present invention has outstanding advantages in the auxiliary treatment of cardiovascular diseases. The use of the device can greatly improve the adhesion rate of the microneedle patch on the myocardial surface and the retention rate of myocardial stem cells, activate myocardial stem cells and accelerate their recovery, thereby improving the growth efficiency of myocardial stem cells.

[0027] (3) The device of the present invention is easy to operate, safe, non-invasive, and has no side effects on the human body. It can achieve the goal of restoring myocardial function in a relatively short period of time and has a significant effect in the auxiliary treatment of cardiovascular diseases such as myocardial infarction and heart failure.

[0028] (4) The bioengineering materials hydrogel and chitosan used in the present invention are non-toxic and harmless to the human body, and after use, they are excreted from the body through metabolic hydrolysis, without the need for removal through minimally invasive surgery;

[0029] (5) The present invention can play a significant auxiliary therapeutic effect. When using the device, the adhesion rate of the microneedle patch on the myocardial surface can be increased, and the retention rate and growth rate of myocardial stem cells can be increased;

[0030] (6) The present invention uses the latest microneedle technology to deliver stem cells, which is better than myocardial injection, achieves targeted delivery of stem cells, and is easy to operate;

[0031] (7) The present invention uses the latest microneedle technology to deliver stem cells, which is better than patch-type tissue engineering materials;

[0032] (8) The present invention is safe and effective, and is suitable for people suffering from myocardial infarction, and has a wide range of promotion and use significance; BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 This is a schematic top view of a chitosan hydrogel microneedle patch device for transporting myocardial stem cells before packaging;

[0034] Figure 2 It is a cross-sectional schematic diagram of a chitosan hydrogel microneedle patch device for transporting myocardial stem cell function before packaging according to the present invention;

[0035] Figure 3 It is a bottom view schematic diagram of a chitosan hydrogel microneedle patch device for transporting myocardial stem cells function after packaging according to the present invention;

[0036] Figure 4 It is a cross-sectional schematic diagram of a chitosan hydrogel microneedle patch device for transporting myocardial stem cells function after packaging according to the present invention;

[0037] In the figure: 1. hollow microneedle; 2. cell lysis pool; 21. substrate; 22. enclosure. DETAILED DESCRIPTION

[0038] The following will be combined with the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0039] The low retention rate and survival rate of myocardial stem cells in the heart are the main obstacles to the current adjuvant treatment of myocardial infarction. This is mainly due to the inability of injected stem cells to find a suitable position in the myocardium and become myocardial tissue and successfully integrate with it. The gel-like material attached to the surface of the myocardium cannot penetrate into the myocardium and can only repair the surface of the myocardium. Hydrogels have been used to improve stem cell transplantation. These hydrogels will form effective cross-links a few minutes after injection to prevent stem cells from migrating from the defective area, resulting in the inability of stem cells to reach the designated area. The hollow microneedles made of chitosan ensure that the device has sufficient hardness to puncture the surface of the myocardium and can firmly fix the patch device on the surface of the myocardium to ensure the precise delivery of myocardial stem cells. In addition, in order to ensure the migration and survival of stem cells, the volume size of the hydrogel is largely limited by oxygen and nutrient requirements.

[0040] Based on the patch-based delivery of stem cells, precise delivery is carried out directly near the damaged tissue area. Patch-based delivery of stem cells to the myocardium refers to the generation of tissue structures in vitro and then transplanted into the body. This technology restores the function of the tissue by growing stem cells on the dominant material, then delivering them to the vulnerable area and integrating them with the surrounding cells. The advantage of patch-based delivery of stem cells is that it can improve the compatibility of stem cells with the surrounding environment by directly contacting the damaged tissue, thereby creating a stable and effective environment, which is conducive to promoting the ability of cells to resist apoptosis, differentiation and tissue reconstruction. In addition, this technology does not require cell preparation and injection, and the operation process is simpler and safer. There are many advantages to the use of a hydrogel microneedle patch that can encapsulate stem cells as a stem cell carrier. The hydrogel has a higher biological activity of encapsulated stem cells and a composition that is closer to human tissue, which significantly enhances the transplantation of infarcted myocardial stem cells and the application of auxiliary treatment of myocardial infarction.

[0041] like Figure 1-4 As shown, the patch device includes hollow microneedles 1 and a cell lysis pool 2 arranged in an array. The cell lysis pool 2 is composed of a substrate 21 and a panel 22. The panel 22 is erected to form a circle. The substrate 21 is arranged at the bottom of the panel 22. The substrate 21 is connected to the top of the panel 22. The cavity formed by the substrate 21 and the panel 22 performs closed packaging for stem cells and nutrients. The root of the hollow microneedle 1 is connected to the substrate 21. The substrate 21, the panel 22 and the hollow microneedle 1 are integrally formed. The array area of ​​the hollow microneedle 1 on the substrate 21 is 1 to 5 cm 2 .

[0042] Among them, the hollow microneedle 1 is composed of a main needle and four auxiliary needles, all of which are shell-like porous structures made of chitosan. The porous structure of chitosan allows myocardial stem cells and nutrients that maintain the survival of stem cells to enter the myocardium by themselves. Chitosan is generally hard and has enough hardness to pierce the myocardial epidermis and form a minimally invasive channel without breaking. Chitosan is easily soluble in water and can be metabolized and absorbed by the human body. Moreover, as the operation proceeds, the chitosan hollow microneedle will gradually dissolve, and more and larger channels will be formed, allowing myocardial stem cells to enter the myocardium by themselves, speeding up the transport speed. Subsequently, the substrate made of chitosan will also gradually dissolve, and the transport efficiency will reach the maximum at this time.

[0043] After maintaining the microneedle channel for a certain period of time, the chitosan hollow microneedle dissolves completely in 10 to 20 minutes, and the microporous microchannels formed on the surface of the myocardium further increase the speed at which myocardial stem cells enter the myocardium.

[0044] The hollow microneedle 1 is conical, triangular or quadrangular, and is arranged in an array on a substrate 21. The height of the hollow microneedle 1 is 0.5-4 mm, the diameter of the needle tip is 50-100 μm, the size of the bottom end of the needle body is 200-500 μm, the shell wall thickness of the hollow microneedle 1 is 500-800 μm, and the distance between two hollow microneedles 1 is 600 μm. The diameter of the hole on the side wall of the shell is 20-50 μm, and the array is distributed on the side wall of the shell. It should be noted that the maximum height of the needle body is 4 mm, the maximum diameter of the needle tip is 100 μm, and the maximum diameter of the bottom end of the needle body is 500 μm.

[0045] The cell lysis pool 2 includes a substrate 21 and a surrounding plate 22, which are mainly used to carry myocardial stem cells and their nutrients. This structure can transport more myocardial stem cells. The substrate 21 is a plate-like porous structure made of chitosan with a thickness of 300-500μm. The hollow microneedle 1 and the substrate 21 are both composed of chitosan, which has a high hardness and can be dissolved in tissue fluid and then metabolized, providing space for the storage and placement of myocardial stem cells. The thickness of the surrounding plate is 500-1000μm, and the surrounding plate 22 is a lysis pool base made of hydrogel, which contains nutrients required for the survival of stem cells, and the required environment such as acidity and alkalinity, which can improve the microenvironment of myocardial infarction and promote the transplantation and survival of cardiac stem cells.

[0046] The present invention uses hydrogel to encapsulate myocardial stem cells, which has great advantages because hydrogel has good encapsulation biological cell activity and its degradation products are non-toxic amino acids, etc. The main function of hydrogel is to encapsulate myocardial stem cells and their nutrients to maximize the activity of stem cells. When the device is attached to the surface of the myocardium, the surface of the substrate 21 begins to melt, forming a channel sufficient for myocardial stem cells to pass through, accelerating entry into the myocardium. Therefore, the present invention uses chitosan to prepare the hollow microneedle 1 and the substrate 21.

[0047] In summary, the hydrogel microneedle patch that transports myocardial stem cells can stay on the surface of the heart for a longer time and does not need to be removed by minimally invasive surgery. It will be decomposed into non-toxic small molecules inside the human body and eliminated from the body. In this way, a better delivery effect is achieved;

[0048] The present invention proposes and designs a hydrogel microneedle device with higher delivery efficiency, cell survival rate, healing ability and myocardial repair ability, which can significantly enhance the effect of auxiliary myocardial treatment and is used to deliver ventricular myocardial cells with biological activity and function. It not only reveals the process of patch delivery of myocardial stem cells, but also the hydrogel microneedle device has the advantages of minimally invasive and less harm to the body compared with previous delivery methods.

[0049] The operation method of a chitosan hydrogel microneedle patch device having the function of transporting myocardial stem cells is as follows:

[0050] First, the stem cells and nutrients that maintain the survival of the stem cells are placed in the cell lysis pool 2. At this time, the device is in the state of Figure 1 As shown, the substrate 21 is in an open state;

[0051] Second, the stem cell packaging is performed by bonding the substrate and the enclosure to complete the stem cell packaging;

[0052] Third, the encapsulated chitosan hydrogel microneedle device is placed in physiological saline for storage. When medical staff need to use the device during surgery, they can directly take it out of the physiological saline and press one side of the chitosan hollow microneedle needle on the surface of the myocardium. The chitosan hollow microneedle has sufficient hardness to pierce the myocardial epidermal cells and form a channel for myocardial cells to pass through. At this time, the myocardial cells enter the myocardium from the through-hole of the substrate through the hole of the chitosan hollow microneedle;

[0053] As time goes by, the chitosan hollow microneedles and substrate will gradually melt, greatly accelerating the speed at which stem cells enter the myocardium;

[0054] Finally, when all myocardial stem cells are delivered, the entire chitosan hydrogel microneedle patch will be broken down into macromolecules inside the body and then excreted from the body with metabolism;

[0055] Compared with the existing technology, the myocardial stem cell transport device can effectively transport stem cells while greatly improving the cell survival rate, retention rate and speed of cell transport.

[0056] The above are only preferred specific implementation modes of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical solutions and inventive concepts of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A chitosan hydrogel microneedle patch device with the function of encapsulating and transporting myocardial stem cells, wherein the chitosan hydrogel microneedle patch device with the function of encapsulating and transporting myocardial stem cells is applied to the surface of the myocardium, characterized in that: include: The cell lysis pool is composed of a base plate and a surrounding plate. The surrounding plates are erected to form a circle. The base plate is arranged at the bottom of the surrounding plates. The base plate is connected to the top of the surrounding plates and performs closed packaging on the myocardial stem cells and nutrients in the cavity formed by the base plate and the surrounding plates. The interior of the closed package has a certain preset pressure; The arrayed hollow microneedles consist of a main needle and four auxiliary needles, which are arranged at the outer bottom of the cell lysis pool, and the roots are connected to the substrate; The hollow microneedle and the substrate are made of chitosan; the enclosure is made of hydrogel; The substrate, the enclosure and the hollow microneedles are formed in an integrated manner; The cell lysis pool is encapsulated by a substrate; The hollow microneedle is a shell-like porous structure made of chitosan. As time goes by, the chitosan hollow microneedle will gradually melt to form a larger channel, thereby increasing the speed at which myocardial stem cells enter the myocardium; the substrate is a plate-like porous structure made of chitosan.

2. The chitosan hydrogel microneedle patch device having the function of encapsulating and transporting myocardial stem cells according to claim 1, characterized in that: The apron is composed of hydrogel with a thickness of 200 to 500 μm; the apron made of hydrogel is coated with myocardial stem cells and nutrients required for the survival of myocardial stem cells, which can improve the microenvironment of myocardial infarction and promote the transplantation and survival of myocardial stem cells in the heart.

3. The chitosan hydrogel microneedle patch device having the function of encapsulating and transporting myocardial stem cells according to claim 1, characterized in that: The hollow microneedle is conical, triangular pyramidal or quadrangular pyramidal, with a height of 0.5-4 mm, a needle tip diameter of 50-100 μm, a needle body bottom size of 200-500 μm, a shell wall thickness of 500-800 μm, and a hole diameter of 20-50 μm on the shell side wall.

4. The chitosan hydrogel microneedle patch device having the function of encapsulating and transporting myocardial stem cells according to claim 1, characterized in that: The thickness of the substrate is 300-500 μm, the thickness of the surrounding plate is 500-1000 μm, and the center distance between two hollow microneedles is 600 μm.

5. A method for operating the hydrogel microneedle patch device having the function of transporting myocardial stem cells according to any one of claims 1 to 4, comprising the following steps: First, myocardial stem cells and nutrients that maintain the survival of myocardial stem cells are placed in the cell lysis pool. At this time, the substrate is in an open state. Second, myocardial stem cell encapsulation is performed by bonding the substrate and the surrounding plate to complete the myocardial stem cell encapsulation and obtain an encapsulated chitosan hydrogel microneedle device; Third, the encapsulated chitosan hydrogel microneedle device is placed in physiological saline for storage. When the device is needed, it is directly taken out of the physiological saline; one side of the microneedle surface is pressed on the surface of the myocardium; the chitosan microneedle has sufficient hardness to pierce the myocardial epidermal cells, forming a channel for myocardial stem cells to pass through. At this time, myocardial stem cells enter the myocardium from the through hole of the substrate through the hole of the chitosan hollow microneedle; as time goes by, the chitosan hollow microneedle and the substrate gradually melt, accelerating the speed at which myocardial stem cells enter the myocardium; Finally, when all the myocardial stem cells are delivered into the body, the entire chitosan hydrogel microneedle patch will be broken down into macromolecules inside the body and metabolized and excreted.

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