Biomaterials and Devices for Disease Diagnosis and Therapy

Lecture Summaries

week #	topics	lecture summaries
1	Introduction to Biomaterials	The first session will begin with instructors and students describing their backgrounds and interests to learn about each other and to ensure that course material and discussions are appropriate and relevant. After introductions have been made, the remainder of the first session will be dedicated to explaining the objectives, format, and material included in the course. We will discuss the syllabus, goals, and expectations for the course, and schedule a permanent meeting time for the remainder of the semester based on student and instructor availability. The instructors will then present an overview of the course material and current state of the field. Special emphasis will be given to biomaterial and device-based technologies that have reached the clinic or are at the cutting edge of research.
2	Vaccine Delivery from Biodegradable Microspheres	This session will explore the encapsulation strategies being used for creating single-injection vaccines. One key challenge in vaccination efficacy and compliance is the need for multiple doses given months apart. While this is not necessarily a major issue in the developed world, it is a major logistical problem in the developing world—where nearly all vaccine-preventable deaths occur. The two papers this week discuss strategies for encapsulating vaccines in materials that degrade over time and release their contents over time in an effort to elicit the same level of immune response generated by current multi-dose vaccination regimens after just one injection. The first manuscript introduces the concept of using polymers to control the release of vaccines over time to eliminate the need for multiple injections administered over the course of months. The second paper describes how natural materials might be able to enhance immunogenicity but present other manufacturing challenges. Key points of discussion will include biodegradation mechanisms, natural versus synthetic materials, microparticle formulation, release kinetics, protein stability, and humoral immunity.
3	Advanced Techniques for Improving Vaccine Efficacy	Vaccines are most commonly delivered via intramuscular injection because of ease of accessibility. However, the muscle does not contain a high concentration of dendritic cells (the cell type that serves as the initial mediator of the adaptive immune system) leading to suppressed responses relative to other administration sites. As a result, novel material-based technologies are being employed to dramatically improve the immune response and thereby enable dose-sparing or adjuvant-free vaccines. The first paper describes the use of microneedles for vaccine delivery and illustrates the benefits of delivering vaccine into skin rather than into the muscle. The second paper employs dendrimers, polymers with a specific branched structure, to encapsulate and deliver mRNA to cells, which subsequently produce the vaccine in the body. Key points of discussion will include resident dendritic cells, intradermal patches, nanoparticle formulation, and nucleic acid vaccines.
4	State-of-the-art Cancer Vaccines (Part 1)	Leveraging the specificity of the immune system to combat cancer has recently garnered intense interest in both academia and industry. One strategy involves priming the immune system with tumor-specific peptides that will then seek out cancer cells, identify them as foreign, and kill them. Another popular strategy is called chimeric antigen receptors (CAR-T therapy), which involves the isolation of a patient’s T cells from blood, genetic modification to introduce a cancer-targeting receptor, and re-infusion of those modified cells resulting in cancer cell death. This paper describes a nanoparticle that targets lymph nodes to improve the immunogenicity of cancer vaccines through non-specific (size-based) and specific (receptor-based) targeting strategies.
5	State-of-the-art Cancer Vaccines (Part 2)	Leveraging the specificity of the immune system to combat cancer has recently garnered intense interest in both academia and industry. One strategy involves priming the immune system with tumor-specific peptides that will then seek out cancer cells, identify them as foreign, and kill them. Another popular strategy is called chimeric antigen receptors (CAR-T therapy), which involves the isolation of a patient’s T cells from blood, genetic modification to introduce a cancer-targeting receptor, and re-infusion of those modified cells resulting in cancer cell death. This paper describes the use of protein nanogels to target T cells in the tumor and enhance the efficacy of CAR-T therapy. Key points of discussion will include tumor-associated antigens, lymph nodes as vaccine targets, and nanoparticles for lymph node trafficking.
6	Diagnostic Tools for Infectious Diseases	Inexpensive, rapid, and early diagnosis of infectious diseases is an urgent unmet need with numerous applications from public health to clinical diagnostics. More than 90% of deaths due to infectious diseases such as acquired immune deficiency syndrome (AIDS), malaria, and tuberculosis (TB) are reported to occur in developing countries, particularly in Sub Saharan Africa. Therefore, the demand for low cost and easy to use diagnostic tools are very clear. Microfluidics technology offers wonderful solutions for development of this kind of device. In this session we review two papers focusing on development of low cost and portable diagnostic tools for detection of HIV and blood stream infection. The first paper by Kang et al presents a new technology capable of selectively detecting bacteria directly from milliliters of diluted blood at single-cell sensitivity. Their process has only one-step and is culture- and amplification-free with the process time around 1.5–4 h. In the second paper, Shafiee et al for the first time demonstrate development of a label-free electrical sensing chip that can detect lysed viruses through impedance analysis.
7	Islet Cell Encapsulation for Diabetes	Diabetes mellitus represents a major global health challenge affecting over 400 million people worldwide. Type 1 diabetes, which represents approximately 10% of all cases, is caused by an autoimmune reaction to the patient’s own beta cells—the insulin-producing cells of the pancreas. Without beta cells, no insulin is produced leading to poorly controlled blood glucose levels and corresponding morbidity or death. Therefore, patients with type 1 diabetes require the administration of exogenous insulin for survival. The encapsulation and transplantation of beta cells has been proposed as a potential cure for type 1 diabetes. However, the immune response to foreign cells and long-term cell viability have proven challenging barriers to implementation. This session will explore beta cell encapsulation and strategies being used to overcome the need for chronic immunosuppression following transplantation. The first paper introduces the concept of cell encapsulation as a strategy to isolate cells from the rest of the body and employs this strategy for blood glucose correction in a diabetic mouse model. The second paper performs a large screen of natural material derivatives and identifies compounds that dramatically reduce the foreign body reaction compared to the original material. Key points of discussion will include autoimmunity, immune suppression, transport through porous materials, chemical modifications to natural materials, and blood glucose regulation.
8	Visit to Sigilon Therapeutics	This session is dedicated to a visit to Sigilon Therapeutics, a Cambridge-based biotechnology company that has developed a super-biocompatible chemistry (Afibromer™) that allows encapsulated cells to avoid a strong foreign body reaction and immune rejection that would otherwise cause them to die. Many patients can benefit from cell-based therapeutics, but fibrosis has presented a barrier to the success of encapsulated cell-based approaches. Using this material, Siglion is developing Living Therapeutics™, in which cells programmed to secrete therapeutic compounds are encapsulated in Afibromer and serve as long-term internal “drug factories” for disease correction. Sigilon’s technology provides a unique, controllable, and dose-adjustable approach to continuously deliver protein therapeutics. The goal of this visit is to put the technology described in the second paper of Session 5 into a direct therapeutic and commercial context and indicate some differences between academic research and industrial development. This experience will include a tour of the lab and a presentation by a Sigilon employee describing the history of the technology, founding of the company, recent growth, product strategy, and regulatory hurdles to commercialization.
9	Tissue-instructive Scaffolds	Because of a worldwide shortage of healthy tissue for transplantation, engineers have explored ways to restore function by regenerating tissue using materials that promote repair. Although the exact strategies used vary by tissue, one key idea is the use of a scaffolding material to guide tissue proliferation and differentiation. Scaffolds have been produced from both natural and synthetic materials with distinct advantages. Natural scaffolds have the advantage of providing complex biochemical and physical cues using endogenous materials, but can exhibit batch-to-batch variability and are more difficult to characterize. Synthetic scaffolds are typically more well-controlled and easier to fabricate, but lack the full complement of cues to guide cell behavior. This session will explore the use of both natural and synthetic materials to create or regenerate tissues for potential transplantation. The first paper describes the decellularization of tissue and use of the remaining extracellular matrix to provide organizational cues to newly introduced cells. The second paper uses a synthetic polymeric scaffold with topographical patterns that guide cell alignment for nerve repair. Key points of discussion will include decellularization, extracellular matrix characterization, scaffold fabrication techniques, and topographical cell-biomaterial interactions.
10	Diagnostic Tools for Cancer	Cancer, if detected early, before it has the chance to spread in the body, is more likely to be treated successfully. In the late stages treatment becomes more difficult or impossible. Microfluidics technology has the potential to provide noninvasive, inexpensive, and informative clinical diagnosis of cancer. Two papers will be discussed in this session. First we will review work by Fan et al, in which they report an integrated microfluidic chip, capable of sampling a large panel of protein biomarkers over broad concentration ranges, within a short time (10 min) of sample collection. This diagnostic tool uses only a drop of blood from a finger prick. The second paper is about a new method for isolation of circulation tumor cells (CTCs). These are cells from a primary tumor that have entered into the vascular or lymphatic systems and are circulated in the body by the blood stream. Isolation and counting of CTCs from blood is a method for cancer diagnostics and also important for monitoring patient treatment. To purify and identify CTCs, protocols based on affinity to cell-surface markers have been used. However, these chemical-based techniques have not been very efficient because of variability of cell biomarker expression associated with tumor heterogeneity and cross-reactivity of antibody probes. This paper reports a label free high-throughput microfluidic chip to isolate, count, and characterize the biophysical properties of CTCs.
11	Low-cost, Paper-based Diagnostic Tools	Diagnostics for the developing world must be low cost, independent of supporting infrastructure, and lightweight. In session 11, we will review a new class of analytical devices fabricated by layering paper that meets these criteria. The first manuscript by Martinez et al describes paper-based sensors developed in the Whitesides group at Harvard. These devices extend paper-based assays from one-dimensional flow systems to 3D devices with complex microfluidic paths and expanded analytical capabilities at very low cost. The second article by Dungchai et al. reports the first demonstration of electrochemical detection (ECD) for paper-based microfluidic devices. ECD is a detection technique based on reading the electrical current generated by electron transfer due to chemical reaction between species. This method has several advantages, like the simplicity of the instrumentation and low electrical power requirements for in-field use. Additionally, while other paper-based sensors work by change of the color and suffer from variation in readout because of the change in ambient light intensity, ECD devices rely on changes of electrical signals and therefore the readout is more reliable.
12	Non-viral Delivery of Genetic Material for Gene Therapy and Cancer	The delivery of macromolecules such as RNA and DNA has numerous therapeutic applications. However, the intracellular delivery of these materials is a very challenging task, since existing vector-based and current viral repurposing and physical methods have limitations, including decreased efficacy over time and cellular toxicity. In this session, we will review two papers describing strategies to transport genetic materials into cells. The first paper by Sharei at al. describes a microfluidic platform for delivery in which cells are deformed mechanically when they pass through a constriction smaller than the cell diameter. The resulting shear forces transient holes in cell membranes and facilitates the transfer of material from the surrounding buffer into the cytosol. The second paper describes the design of lipid nanoparticles to optimize lymph node targeting to promote a strong T cell response against cancer cells.
13	Oral Presentations, Conclusion, and Closing Remarks	Students will give oral presentations (~ 20 min) about their chosen research papers and lead critical discussions about the papers’ findings. We will have a final discussion about what we have learned about biomaterials and devices for disease diagnosis and therapy, the challenges of the field, and future directions. Finally, students will complete course evaluations and provide feedback to the instructors.