Tag Archives: diabetes

Introduction to promising treatment for type I diabetes

Cell therapy became a hot topic since chimeric antigen receptor (CAR) T-cell therapy was approved by U.S. Food and Drug Administration (FDA) for acute lymphoblastic leukemia and lymphomas. It is a milestone for cancer treatment, but cell therapy is also a promising solution for type 1 diabetes (T1D) patients. According to American Diabetes Association, nearly 1.6 million Americans had T1D in 2018. In each year, there are around 64,000 people diagnosed with T1D in the United States. Moreover, scientists and doctors predict that there will be 5 million T1D patients by 2050 in the United States. Additionally, according to American Diabetes Association, two different methods are used to identify diabetes, glaciated hemoglobin (A1c) test, and blood glucose test. The glaciated hemoglobin (A1c) test could indicate the average level of blood glucose in the past two to three months. The A1c level is divided into three intervals: A1c level below 5.7 is considered normal, between 5.7 and 6.4% is identified as pre-diabetes, and over 6.5% is diagnosed as diabetes. In blood glucose tests, there are three different methods to measure blood glucose: 1. Random blood glucose test: a blood sample is collected without fasting before the test, and the blood glucose less than 200-milligram per deciliter (mg/dL) is identified as normal. 2. Fasting blood glucose test: a blood sample is collected after overnight fasting. The blood glucose less than 100 mg/dL is normal, and between 100 and 125 mg/dL is considered pre-diabetes. When the blood glucose is higher than 126 mg/dL is diagnosed as diabetes. 3. Oral glucose tolerance test: After the fasting blood glucose test, a sugary solution would be provided for oral consumption. Several blood glucose tests would be measured for the next two hours. A blood glucose level less than 140 mg/dL is normal, and a level between 140 and 199 mg/dL is considered pre-diabetes. A level over 200 mg/dL is diagnosed as diabetes.

Four different tests are usually used to diagnose diabetes: Glycated hemoglobin (A1C) test, random blood glucose test, fasting blood glucose test, and oral glucose tolerance test.


T1D is an autoimmune disease; the patients’ immune system cannot recognize their own cells/tissue and attack them. In the human body, the pancreas plays an important role in maintaining the blood glucose level by two hormones, insulin, and glucagon. After each meal, blood glucose increases, and insulin is secreted to lower blood glucose. On the other hand, when a person feels hungry and the blood glucose is lower than the normal level, the alpha cells in the pancreas will secret glucagon to increase blood glucose level. However, in T1D, the pancreas is no longer functional to respond to dynamic blood glucose. In T1D patient’s daily life, insulin injection is required after every meal to prevent high glucose levels, which might cause cardiovascular disease. Up to date, researchers have been developed two potential treatments for type I diabetes, cell therapy, and artificial pancreas.

Islet cells in pancreas are comprised of different cell types: alpha cells, beta cells and delta cells. Additionally, alpha cells could respond to hypoglycemia (low blood sugar) by glucagon secretion, and beta cells could secrete insulin while hyperglycemia occurs. However, the alpha and beta cells are detroyed by T1D patient’s immune system and the body would lose the ability to maintain blood glucose level.

In cell therapy, it is a simple idea that we could transplant the pancreatic cells to replace the destroyed cells; however, the transplanted cells would be attacked by the patient’s own immune system again. To solve this, many researchers have been worked on cell encapsulation to protect the cells from immune cells attack. In 2015, Prof. Minglin Ma and his group at Cornell University developed a novel design to incorporate nano-fiber and hydrogel together to protect the pancreatic cells by hydrogel and enhance the mechanical property by stiff nano-fiber. In 2018, a retrievable and scalable cell encapsulation device was designed for the potential treatment of type I diabetes. The common design of these potential therapeutics is that the hydrogel material could not only protect the cells from antibody attack but also allow the mass transfer, such as nutrients, oxygen, insulin, to respond to blood glucose. Therefore, the transplanted cells could respond to the blood glucose immediately. On the other hand, the artificial pancreas is another option to treat type I diabetes with precise control release of insulin and glucagon to maintain blood glucose. Two methods we could use to manipulate the release, chemically and electronically management. In chemically management, a smart hydrogel is designed and synthesized to respond to the blood glucose in material property change to release glucagon in low plasma glucose and insulin in high plasma glucose. For instance, in 2020, Prof. Zhen Gu and his team at UCLA developed a dual responsive micro-needle system to manage blood glucose levels. Although the chemically responsive design is an intelligent approach to deliver the therapeutic peptides, the delivery of peptides relies on mass diffusion, which might not be effective immediately. In the electronically management, electronical device could measure the blood glucose in real time and inject the insulin or glucagon directly. However, the embedded needle of the electronical device need to be replaced every 2-3 days. In sum, cell therapy and artificial pancreas could be promising solutions to treat or “cure” type I diabetes in the future.

Hydrogel could protect the encapsulated cells from immune system and the porous structure allows mass diffusion of nutrients and waste.

Reference:

  1. Centers for Disease Control and Prevention (CDC), Nataional Diabetes Statistics Report, 2020
  2. American Diabetes Association, Statistics About Diabetes
  3. D. An et al. Developing robust, hydrogel-based, nanofiber-enabled encapsulation devices (NEEDs) for cell therapies, Biomaterials 2015
  4. D. An et al. Designing a retrievable and scalable cell encapsulation device for potential treatment of type 1 diabetes, Proceedings of the National Academy of Sciences 2018
  5. Z. Wang et al. Dual self-regulated delivery of insulin and glucagon by a hybrid patch, Proceedings of the National Academy of Sciences 2020

Jason(Yen-Chun) Lu, All right reserved.

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What engineers can do in biomedical field?

An engineer is trained to solve problems through science and math. We can see engineers everywhere in our lives, such as civil engineers, chemical engineers, electrical engineers, and software engineers, to improve our daily lives. What can engineers do in the biomedical field? A pioneer, professor Robert Langer, an internationally well-known biomedical engineer and inventor, is a perfect example illustrating how engineers can contribute to biomedical science. Dr. Langer holds the title of David H. Koch Institute Professor at the Massachusetts Institute of Technology (MIT) as well as that of Senior Lecturer on Surgery at Harvard University’s Medical School. It is worth to mention that being an Institute Professor at MIT is the highest honor that can be awarded to a faculty member. Besides, Dr. Langer has more than 1,500 published papers and over 1,400 issued patents and pending patents worldwide. In his research, he focuses on solving biomedical problems from an engineering aspect, such as developing materials for drug delivery, cell engineering, and tissue engineering. Here we have some examples to demonstrate how engineers contribute to the field.

First, Dr. Langer and his colleagues with Bill & Melinda Gates Foundation created pulsatile-release PLGA microspheres for single-injection vaccination1 for developing world. Poly (lactic-co-glycolic acid) (PLGA) is an FDA-approved degradable material for clinical application, and core-shell decoupled microspheres are fabricated by a new microfabrication method (StampEd Assembly of polymer Layers (SEAL))2. Despite the immense increase in vaccine coverage worldwide over decades, vaccine-preventable infectious diseases still claim the lives of approximately 1.5 million children every year because of inadequate distribution and administration of vaccines in the developing countries. Currently, around 19.4 million infants do not receive fully immunized against diphtheria, tetanus, and pertussis. Moreover, 6.6 million of them with one dose of the vaccine remain at risk for these diseases due to lack of full series of doses. With the pulsatile-release PLGA microspheres and SEAL technology, the problem of inadequate distribution and administration of vaccine could be solved, and millions of people in the developing world would benefit.

What engineers can do in biomedical field? 1

Fig. 1, Using different molecular weight of PLGA to control degradation time to release the therapeutics to evoke immune response. (modified from McHugh, K. J. et al. Science, 2017).

Second, Dr. Langer and his colleagues discovered three chemical materials which can suppress foreign body response to minimize fibrosis in rodents and at least 6 months in non-human primates3. These materials were conjugated to alginate hydrogel, and these hydrogel microspheres were transplanted in mice and monkeys. In addition, these anti-fibrotic materials could be applied in cell therapy, such as beta cell replacement treatment for type I diabetes. In type I diabetes, patients’ pancreatic islet cells are destroyed by their own immune system. To date, the most common treatment is a daily insulin injection to control blood glucose. However, insulin injection cannot cure type I diabetes or prevent the many devastating diseases associated with diabetes, such as blindness, hypertension, and kidney disease. Islet cell transplantation could provide an alternative treatment for type I diabetes to avoid daily injection and restore normoglycemia. However, foreign body response is a major challenge for cell therapy. The cellular and collagenous deposition would isolate the transplanted device from the host, which could induce tissue distortion, cut off the nourishment of encapsulated cells, and finally lead to device failure. With these new anti-fibrotic materials, the transplanted device with insulin-producing beta cells could maintain its function in the long term to cure type I diabetes.

What engineers can do in biomedical field? 2

Fig. 2, Three chemical materials can suppress foreign body response to minimize fibrosis in rodents and non-human primates. Encapsulated by these materials, the therapeutic cells can be protected from host immune system and also suppress its immune system to reduce foreign body response.

Third, Dr. Langer’s group developed a combinatorial library of ionizable lipid-like materials to identify mRNA delivery vehicles that facilitate mRNA delivery in vivo and provide potent and specific immune activation4. The cationic lipid-like materials could encapsulate therapeutic mRNA in lipid nanoparticles by electrostatic interaction. To date, mRNA therapeutics is a promising strategy for disease treatment and vaccination. In contrast to DNA therapeutics, mRNA delivery results in transient expression of encoded proteins, and so avoids complications associated with insertional mutagenesis. Currently, mRNA therapeutics, including disease treatment and vaccination, are in the process of clinical trials. For instance, TranslateBio has conducted phase ½ clinical trials in delivering mRNA encoding fully functional cystic fibrosis transmembrane conductance regulator (CFTR) protein to treat cystic fibrosis by nebulization. For COVID-19, Moderna (co-founded by Dr. Langer) and Pfizer all utilize lipid nanoparticles to deliver mRNA encoding for a prefusion stabilized form of spike protein. Moderna also has two mRNA cancer vaccines in phase 1 and phase 2 to target solid tumors and melanoma. These clinical trials with mRNA delivery are incorporated to cationic lipid-like materials to enhance mRNA stability and lead to an increase in intracellular protein expression.

What engineers can do in biomedical field? 3

Fig. 3, Illustration for the formulation of lipid nanoparticles in mRNA delivery

In sum, biomedical engineering is a combination of multiple disciplines, such as engineering, biology, medical science, and chemistry. To date, biomedical engineers have contributed to the biomedical field in different aspects, such as new materials, fabrication methods, and medical devices to improve current medical treatments and solve emerged medical problems, for instance, COVID-19.

Reference:

1.        Guarecuco, R. et al. Immunogenicity of pulsatile-release PLGA microspheres for single-injection vaccination. Vaccine 36, 3161–3168 (2018).

2.        McHugh, K. J. et al. Fabrication of fillable microparticles and other complex 3D microstructures. Science (80-. ). 357, 1138 LP – 1142 (2017).

3.        Vegas, A. J. et al. Combinatorial hydrogel library enables identification of materials that mitigate the foreign body response in primates. Nat. Biotechnol. 34, 345 (2016).

4.        Miao, L. et al. Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation. Nat. Biotechnol. 37, 1174–1185 (2019).

Jason(Yen-Chun) Lu, All right reserved.