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As our project nears completion, the AFCM-Egypt iGEM team recognizes the importance of considering the real-world implementation, future applications, distribution, and logistics of our work. Given our end users are patients, it is imperative to provide a comprehensive overview of the targeted burn wounds. Moreover, discussing the prevalence and incidence of this disease is crucial, as these factors were instrumental in our selection. We found that the incidence of burn injuries greater than that of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and tuberculosis combined and also approached the incidence of all malignant neoplasms. Thus, we decided to work on a cure that rapidly heals burn wounds.
Generally, burn wounds are characterized by loss of skin, infection, inflammation, and pain. Current treatment often involves wound care, fluids for rehydration, and pain relieving medication. Severe burns may require skin grafting, hyperbaric oxygen therapy, and antibiotics. Long-term recovery may involve rehabilitation to address scarring, contractures, and psychological trauma.
We intend to provide a novel burn wounds treatment based on local delivery of engineered mesenchymal stem cells (MSCs) ,which are stromal cells that can self-renew and also exhibit multilineage differentiation, with some bioactive materials in a hydrogel scaffold. Our treatment SONG-H (Stem cell-based Occlusive Nutritive Gel of Healing) is part of a kit that covers burn wounds, promotes epithelialization, prevents infection, keeps wounds moist, reduces pain, and minimizes scarring. It is a topical hydrogel scaffold that carries engineered mesenchymal stem cells. This hydrogel dressings are multifunctional as it plays therapeutic roles mainly from three aspects: preventing infections, promoting repair, and constructing scaffolds for skin tissue engineering. Plus, it is non-toxic, does not cause inflammation, retains moisture, absorbs wound exudate, maintains skin physical and mechanical integrity and promotes cellular functions as well as reduces the temperature and pain of the wound.
The MSCs are engineered to increase YAP-1 expression which helps to deal with loss of skin through increasing skin proliferation and cell differentiation. At this point, the control of MSCs activity is mandatory to prevent any unwanted YAP-1 side effects. This is achieved through the innate nature of YAP-1 as its activity is suppressed in response to cell to cell mechanical contact. Moreover, we added a transcription activator receptor that is constrained to the presence of tissue injury specific biomarker called VEGF (vascular endothelial growth factor). Furthermore, we aim to treat loss of skin by exploiting MSCs’ ability to communicate with other cells through exosomes to increase YAP-1 expression in the surrounding local cells. Especially that exosomes have the ability to secrete various biologically active molecules which can regulate the responses of surrounding cells. So, we have implemented YAP-1 mRNA inside the exosomes with a protein – specific RNA switch depending on MMP-9 (intracellular tissue injury biomarker). In the kit, there is a bactericidal topical agent to prevent infection resulting from skin discontinuity. To ensure healed skin vitality, we considered nutritional elements like zinc, vitamin E, vitamin C to improve wound healing and immunity. We added a systemic analgesic anti-inflammatory drug in our kit to reduce pain and inflammation.
The design includes two main stages:
The pre-clinical study is divided into two stages: in vitro study in addition to in vivo study.
In our approach, we needed to validate each sector separately, as follows:
Our in vivo study will be conducted on animal models. By analysis, the gold standard animal model for burn treatment is rats, as rats are characterized by reduced healing time. This feature makes it easy for researchers to follow the rat very closely and enables them to study wound healing mechanisms rapidly and efficiently. The other advantages of using rats in burn studies are their availability and their cost-effectiveness. Moreover, rats also share several physiological similarities with humans, and relevantly rats’ skin is composed of the dermis and epidermis. However, some substantial differences need to be considered as dermal and epidermal thickness, scar formation, and glucose metabolism post-burn injury. Also, rats heal by wound contraction, instead of healing by re-epithelization in humans.
Our approach will be done on second-degree burn rats, by application of hydrogel containing MSCs to improve MSCs bioactivity and skin repair function in our studies. This can be achieved by improving the engraftment and survival rates of transplanted MSCs. Our study is considered a new assay so it will require new validation cycle through the three stages of validation; pre-study validation, in-study validation & cross-validation to confirm the biological and pharmacological activity of our approach. Also, measuring the outcome of MSCs application as the time, rate of wound healing, the proportions of wound contraction and re-epithelialization, the Vancouver scar scale, functional squealae, and the incidence of treatment-related side effects (pain, bleeding, and infections) at the end of this study.
The pre-study validation is required before implementing the assay to identify the best design for our approach. Our study design will be a parallel group with dependent/outcome variables. Then in-study validation our approach will be tested to provide a preliminary assessment of our drug efficacy, the best time of application, and route of administration, also enable us to know the minimum and maximum dose for ideal treatment with fewer side effects. The validation cycle later ends with cross-validation in which our approach will hand off to another screening center where the final validation of our entirely new assay, as our approach will require replicate determination study (tier2) for full validation. At the end of the validation cycle of the approach, our drug will be ready for clinical study.
According to the Food and Drug Administration (FDA) , pre-clinical research provides essential data on drug safety but is not enough to bring the drug to market. To validate the safety and efficacy of a new drug, a clinical trial is necessary. The term "clinical trial" refers to studies conducted on human participants to explore the possible and unpredictable interactions of the drug with the human body. Before starting a clinical trial, we must submit an Investigational New Drug (IND) application to the FDA. This application should include the following:
-Animal study data and toxicity data: Results from pre-clinical studies that demonstrate the drug’s safety and identify any harmful side effects. - Manufacturing information: Detailed documentation on the drug’s production process, including quality control measures and consistency across batches. - Clinical protocols (study plans): A comprehensive outline of the proposed study, including design, participant criteria, dosing, and safety monitoring. - Data from any prior human research: Any previous studies involving humans should be included to support the application. -Information about the investigator: The qualifications and credentials of those conducting the trial.
After submitting the IND application and receiving approval, we will move into the clinical trial phase. This phase is composed of four stages, each involving a different number of participants based on the specific data needed from each stage:
- Phase 1: A small group of healthy volunteers or patients is involved to assess safety, determine safe dosage ranges, and identify potential side effects. - Phase 2: A larger group of participants is used to further assess the drug’s effectiveness and monitor its safety. - Phase 3: This phase involves an even larger population to confirm the drug’s efficacy, monitor adverse reactions, and gather more comprehensive safety data. - Phase 4: Post-marketing studies are conducted after the drug’s approval to collect additional information on long-term risks, benefits, and optimal use.
In recent updates, the FDA has emphasized several key factors for clinical trials. One of the factors is the need for greater diversity in trial participants to ensure that results are generalized to a broad patient population. Additionally, there is a growing focus on patient-centered trial designs, ensuring that patient input is considered in the trial process. The FDA has also increased its focus on data integrity, requiring strict adherence to guidelines for data collection, storage, and reporting.
Maintaining alignment with these updated FDA guidelines, particularly regarding participant diversity, patient-focused design, and data transparency, is essential for the successful conduct of our clinical trial and the eventual approval of the treatment for burns.
The Federal Food, Drug, and Cosmetic Act (FD&C Act), along with the regulations in Title 21 of the Code of Federal Regulations (21 CFR) Parts 1-58 and 800-1299, establishes the legal framework for regulating medical devices marketed in the United States. The safety and efficacy of a medical device are the primary factors determining its regulatory control and the pathway to market. To bring the SONG-H medical device to the U.S. market, four essential steps must be followed, incorporating the latest updates from the FDA:
This step involves two critical processes. First, we must confirm that our product meets the legal definition of a medical device as outlined in Section 201(h) of the FD&C Act. Once confirmed, we classify our product into one of three categories based on the associated risk level. According to Section 201(h) of the FD&C Act, SONG-H are considered medical devices. Based on the Product Classification Database, our product falls under Class III, indicating the highest risk level in device classification.
Recent updates emphasize the importance of accurately classifying the device and understanding the applicable controls, as this step directly influences the regulatory pathway and the type of data required for subsequent steps. The FDA has heightened its focus on ensuring that high-risk devices, particularly those in Class III, undergo rigorous evaluation to confirm their safety and efficacy before reaching the market.
The type of premarket submission required is determined by the classification of the product established in the previous step. Since SONG-H is classified as a Class III device with the highest risk, we must prepare two specific types of submissions: the "Request for Evaluation of Automatic Class III Designation" under 513(f) De Novo Request, and a "Premarket Approval" (PMA).
The FDA's updated guidelines emphasize the need for thorough and accurate premarket submissions, particularly for Class III devices. There is an increased scrutiny on the quality of the data provided, and the submission must clearly demonstrate the device’s safety and effectiveness. The FDA also encourages the use of new submission tools like eSTAR (Electronic Submission Template and Resource) to streamline the process and enhance the quality of submissions.
In this step, all necessary documentation and fees required for the premarket submission must be meticulously prepared. This includes:
After the premarket submission is complete, compliance with additional regulatory controls is necessary. This includes registering the manufacturing establishment with the FDA and listing the device in the FDA's database. This step ensures that the device is properly documented and tracked in the regulatory system.
The FDA’s recent focus on post-market surveillance and ongoing compliance highlights the importance of this step. Once a device is on the market, it must continue to meet safety and efficacy standards, and must be monitored by the FDA for any issues that may arise. Establishing a strong compliance framework from the beginning is critical for ensuring the device remains in good standing with regulatory authorities.
By following these steps and integrating the latest FDA updates into our process, we can navigate the complex requirements for bringing the SONG-H medical device to the U.S. market. Compliance with these guidelines will help ensure the device's safety, efficacy, and successful market authorization.
There are several methods for burn treatment, the gold standard of which is surgical operations such as skin grafts and plastic surgery, but they have many side effects that range from bleeding in the wound area to loss of sensation at the wound area. Moreover, there are many pharmaceutical medications that are used for burn patients, such as painkillers, antidepressants and antibiotics.Indeed, these medications treat burn symptoms only and are not a radical solution. Furthermore, physiotherapy is provided to prevent contracture and facilitate joint movement if the joint is burned. In the last few years, there are new applications for burn treatment like Nanotherapy which has potential ability for burn treatment;but it is expensive and unavailable.
The gold standard method as we mentioned above is Reconstruction surgeries as Skin grafting. It is an invasive surgical procedure which involves transplanting skin from a donor site to the affected area. The donor site could be from the patient’s own body or from a human or animal donor. Also, these surgeries carry limitations such as donor site discomfort, limited availability of donor skin , expensive to patient and the hospital, and graft failure. Skin grafting is also considered an invasive procedure which isn’t favorable by most patients and ,on the long run, may cause skin contractures,hypertrophic scars, pain, and cosmetic disfigurement.
On the other hand, SONG-H offers a radical solution to burns by application of genetically modified mesenchymal stem cells to enhance wound healing and to reduce the occurrence of wound complications such as contracture, keloid and hypertrophic scarring. Also, It is available, more efficient and cost-effective when compared to other available treatments.
Annual deaths resulting from burns are estimated at about 180,000 Death yearly and burn injuries are a significant public health problem in Egypt. Egypt has one of the highest rates of burn-related deaths worldwide. The prevalence of burns is notably higher in developing countries compared to many developed countries. This is attributed to various factors, including: Socioeconomic conditions such as poverty, cultural practices like traditional cooking methods, and Limited awareness to burn prevention and first aid. So, the implementation of our project in Egypt has a great role in the burn treatment. Generally, developing personalized stem cell banks is a crucial step to provide stem-cell based therapy. Later on, we may add a new department for modifying and engineering these stem cells. Engineered Mesenchymal stem cells have special requirements to be synthesized (cell source, media, temperature, technicians, and biological parts), and to be stored. Moreover, we need to raise people’s awareness for burn first aid and how to react to a burn injury as it can potentially save the victim’s life and minimize damage to their skin.
All of this would happen through advertisements, brochures, and educational sessions in primary health care centers. In tertiary health care and specialized centers, our therapy will be provided as a treatment to improve the burn outcome. We can implement our project more accurately locally and globally, respectively, with the support of the Egyptian Ministry of Health and WHO.
Our target is to give the burn victims a better solution through SONG-H that mediates earlier wound closure, minimizes the complications and heals cosmetically better with minimal scarring. This will occur by applying the gel locally in hospitals taking care of contamination to guarantee the treatment quality, training staff to deal with stem cells as well as ensuring available biological parts to produce SONG-H.
To implement our project, there will be a short term plan to validate SONG-H and get FDA approval. After that, settling on a long term plan can be named as future considerations. Firstly, our vision is to manufacture a platform for regenerative medicine. The start of our project on the simplest cells in the body, which is the skin, but the hope is that the platform will be for all tissues and cells so that they include cells that are not capable of division or renewal in addition to being of complex structure, such as the heart, joints and nerves, as they have many cell lines. Furthermore, we hope to make tissue banks for all types of tissues In the future.
To implement our therapeutic approach in a community, there are a lot of challenges that we need to be aware of to make its implementation easier and increase the efficacy of the treatment. We thought about the challenges that may face us during the early stages of the usage of our SONG-H: