Development of Autonomous Control Mechanism for Patients Suffering Glycemic Abnormalities as a Result of Traumatic Injury or Critical Illness

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1 Development of Autonomous Control Mechanism for Patients Suffering Glycemic Abnormalities as a Result of Traumatic Injury or Critical Illness Hava Siegelmann, Ph.D. Program Manager Information Innovation Office 1

2 Objective Develop multi-hormonal glycemic control solutions (mechanical or bio-engineered) to: Improve patient outcomes stemming from traumatic pancreatic injury/loss, during critical illness and for long-term therapeutic maintenance Daniel 21 years old Daniel suffered traumatic abdominal injury (~20% of battle injuries) from IED shrapnel in Afghanistan result: complete loss of pancreas Unable to control blood sugar, fat gain, cannot digest, neuropathy, altered heart function Medication: Insulin (and digestive enzymes) Nathalie 8 years old Hypoglycemia (excessive insulin): altered mental status, seizures, coma, death Hyperglycemia (insufficient insulin): ketoacidosis, kidney failure, nerve/retinal damage (blindness) vascular disease (stroke) Amount of medication needed today may vary from yesterday Nathalie was born with congenital Hyperinsulinism necessitating complete pancreatectomy Though Nathalie suffered from a genetic mutation rather than a traumatic injury, she has the exact same symptoms, health issues and risks as Daniel. 2

3 The Challenge Dysregulation of blood sugar levels can cause coma, organ failure, heart disease, stroke, a reduction in ability to heal wounds, and death ---- Control of BSL dramatically decreases morbidity and mortality Traumatic Pancreatic Injury (7% of battlefield injuries) Acute/Chronic Disease, Pancreas removal, Wound Healing Surgical Suite Congenital HI, pancreatitis necessitates complete pancreatectomy Burns Diabetes (>100M in US) ICU Images Traumatic pancreas: Wound healing: Burns: Surgical Suite: ICU: Congenital: hxxxps://xxx.hpbonline.org/article/s x(15) /fulltext Need to develop solution for battlefield medical operations, surgical/icu suites, wound healing, and to treat acute/chronic disease that arises from traumatic pancreatic injury, or pancreatic pathologies 3

4 State of the Art (SoA): External Insulin Administration Insulin therapy insulin reduces BSL when high. When low: take sugar, juice What if overnight? If sensor is wrong? Cadaver beta cell injection to liver. But immunesuppressants are necessary Current Research: Improved BSL sensors Packaging beta cells for surgical insertion, sub-cutaneous or abdominal Single Hormone (insulin) Therapy Dual Hormone (insulin & glucagon) Therapy Limitations Pancreas secretes other hormones which are part of the glycemic control system: chief - Glucagon When BSL low Glucagon frees available sugar from liver (glycolysis) and fat (lipolysis) rapidly increasing BSL Insulin-only solution leads to fat gain, reduction of heart adaptivity (aerobic) and RISK when control system fails Betabionics 4

5 We need dual-hormone / med systems Non-functioning or missing pancreas Orphan group ignored by forprofit companies (smaller market than diabetics) - solutions may be more straightforward Save patients suffering critical illness that affect BSL, healing/recovery: wounded and burn victims Improve treatments for Type I and II diabetics: Solution for non-workingpancreas patients will lead to far better diabetes solution (increase lifespan, improve organ health, avoid obesity and long-term disease) 5

6 STTR Structure: Challenges and Phasing Complete reliable closed-loop control system: Sensing Dual hormone/drug therapy Proposers must: Develop both monitoring and delivery together in a single autonomous closed loop system Avoid need of immune-suppressants Solution 1: Mechanical/computational approach with embedded machine learning techniques Solution 2: Biologically engineered multi-hormone system, e.g., organoid-based Ectoderm Hemangioblast +Gata6 Mesoderm (16) (15) (1) (19) (17) hips Medsoendoderm (2) Definitive endoderm (3) Foregut endoderm (4) Pancreatic Organoid Lineage Tree Multi-cells and vascularization Next-Generation Blood Sugar Regulation Phase I Solution 1 Solution 2 Phase II Conduct pre-clinical and/or clinical efficacy studies Phase III Apply device in Target DoD programs Hematopoietic Endothelial Hepato/pancreatic (20) (21) (18) (5) Stellate / Pericyte cells Erythrocytes Endothelial cells Pancreatic (10) (6) Endocrine Exocrine (14) (11) (8) (7) Other pancreatic cell types ( PP Beta cell / 1 Ductal cell Acinar cells (12) (9) Beta cell / 2 (13) Beta cells Ductal cells Images: Weiss laboratory, MIT 6

7 STTR Phase I: Develop POC Capability I II III Choice 1: Mechanical/Computational Prototype Deliverables: Generation of biocompatible device specifications, including Machine Learning (ML)/adaptive control algorithms Development of Proof of Concept prototype Prototype should be tested against and meet design specifications Device should demonstrate capability of injecting the correct hormone/drug based on glycemic environment Choice 2: Biological Engineered Prototype Deliverables: Generation of viable, human autologous pancreatic organoids consisting of (at a minimum) pancreatic alpha and beta cells from ISPCs or stem cells Development of Proof of Concept prototype Provide evidence (morphological, histological, biochemical) that organoids produce appropriate hormones based on glycemic environment Specify plans for improving yield to achieve sufficient organoids for testing in Phase II 7

8 Phase II: Pre-clinical or clinical feasibility studies I II III Choice 1: Mechanical/Computational Solution Deliverables: Prepare regulatory documentation related to FDA (IND) submission as appropriate Pre-clinical or clinical feasibility studies as appropriate (safety, efficacy) Refine reliable, multi-hormonal (or multi-drug) autonomous glycemic control system based on results of pre-clinical and/or clinical feasibility studies. In particular improve ML/adaptive control algorithms as indicated Documentation and/or publication of results from pre-clinical or clinical feasibility studies Choice 2: Biological Engineered Solution Deliverables: Improve production of Organoids to levels that enable pre-clinical studies Verification of hormonal response to glycemic environment Estimate size and number of organoids required for efficacious pre-clinical studies Method of biocompatible delivery in test subject (e.g., encapsulated subcutaneous implantation, direct in vivo implantation, or via scaffold implantation) Prepare regulatory documentation related to FDA (IND) submission as appropriate Pre-clinical or clinical feasibility studies as appropriate (safety, efficacy) Documentation and/or publication of results, if relevant preparation for FDA approval 8

9 Phase III (Suggested) I II III All challengers are encouraged to Translate results into commercial biotechnologies and pharmaceutical applications Create novel microsystem for blood sugar maintenance Facilitate commercial development Requirement Obtain external funding Private Sector Commercialize outside of STTR program Goal of commercialization of Phase II project for sale in military or commercial markets

10 SBIR Structure: Deliverables and Funding Phase Deliverables Funding 1 Mechanical/computational approaches must demonstrate the ability to continuously adapt delivery of appropriate hormone levels or drugs in a closed loop system based on rapidly changing blood sugar levels. Biologically engineered approaches must demonstrate the ability to produce an autologous, multi-hormonal pancreatic organoid consisting (at a minimum) of pancreatic alpha and beta cells. $225k for 10 mo. 2 3 Mechanical/computational approaches will refine algorithms based on studies and will conduct pre-clinical or clinical feasibility studies as appropriate. Biologically engineered approaches will continue refinement of autologous, multi-cell type organoid production, viability, and function. Pre-clinical or clinical feasibility studies will be performed as appropriate. Translate technologies into commercial product and clinical applications $1M for 24mo. $500k for 12mo. option No Direct Monetary Support 10

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