SBIR-STTR Award

Esophageal Atresia (EA) is a congenital birth defect characterized by a discontinuity of the esophagus. Each year several thousand children are born within the EA spectrum. Babies born with EA have trouble feeding, and require a procedure to correct the abnormality. The best treatment for EA is surgery reconnecting the two ends of the esophagus to each other. In some children, however, the gap between the two esophageal ends is too long to be easily connected. This condition is known as long-gap esophageal atresia (LGEA). Current surgical options available for the treatment of LGEA focus upon either the replacement of the esophageal tissue with other autologous tissue, or mechanically stretching the current esophageal tissue to bridge the gap. Although there are several techniques available, there is little consensus about the optimal repair of LGEA. In addition, the infrequent occurrence of LGEA also means that development of improved techniques is greatly hampered. Thus, there is clearly an unmet clinical need for effective methods of esophageal repair. To answer this unmet medical need, Biostage Inc and our academic partners at Connecticut Children’s Medical Center (CT Children’s) propose to develop a novel tissue-engineered esophageal implant that combines a synthetic scaffold with patient derived stem cells, as a treatment for LGEA. Biostage's Cellspan Esophageal Implant has the unique ability to induce the body's own repair mechanism, while providing spatial cues to assist regeneration. Previous preclinical studies at Biostage have established that full-thickness circumferential esophageal defects can be treated by implanting the CEI in an adult pig model. Studies at the Finck laboratory have shown that autologous epithelial cell seeded scaffold can be utilized to treat similar defects in a piglet model. Based on these findings we plan to develop a novel tissue engineered esophageal implant to address LGEA in newborns. The goal of the project will be establishing long-term efficacy of our CEI as an esophageal replacement in piglet pediatric model. Phase I will include the preparation of CEI with size relevant for a pediatric model (Specific Aim #1). We will create a CEI by seeding piglet cells on 3D scaffold in bioreactor and analyze the CEI to determine cell viability, cell penetration and cell functionality in terms of MSC marker expression and cytokine secretion profiles. In Phase II we will perform a short-term in vivo feasibility study of CEI as an esophageal replacement in a piglet model (Specific Aim #2). Once we confirm that no acute adverse effects arise due to animal exposure to the CEI, we will conduct a long term in vivo study (Specific Aim #3), where we will follow the growth and devel- opment of the tissue in the implant zone. The ability of the animals to function normally at such longer time scales will be key to assess the use of the CEI as an esophageal treatment. Upon completion of these Aims, we will initiate dialogue with the FDA to obtain pre-IND guidance and will carry out pre-clinical studies to ensure a clinical path for the use of CEIs as a treatment for pediatric atresia. .

Public Health Relevance Statement:
NARRATIVE long-gap esophageal atresia (LGEA) is a congenital birth defect characterized by a discontinuity of the esophagus, where the gap between the two esophageal ends is too long to be easily connected.There is little consensus about the optimal repair of LGEA and its infrequent occurrence means that development of improved techniques is greatly hampered. In this Fast-Track SBIR application Biostage is seeking to develop a retrievable autologous bioengineered esophageal implant, as a novel treatment for long-gap esophageal atresia.

Project Terms:
Acute; Address; Adipose tissue; Adult; Adverse effects; Affect; AlamarBlue; angiogenesis; Animal Model; Animals; Autologous; base; Biological Assay; Biomedical Engineering; Bioreactors; Cell Adhesion; Cell physiology; Cell surface; Cell Survival; Cells; Child; Childhood; Clinical; Clinical Paths; Congenital Abnormality; Connecticut; Consensus; Cues; cytokine; Defect; design; Development; Engineering; Ensure; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelial Cells; Esophageal; Esophageal Atresia; Esophageal Diseases; Esophageal Tissue; Esophagus; Event; Excision; Exposure to; Family; Family suidae; Feasibility Studies; feeding; Flow Cytometry; Food; Future; Glucose; Goals; Growth; Growth and Development function; Healthcare Systems; Histologic; Implant; implantation; improved; in vivo; in vivo evaluation; Individual; Inflammation; Inflammatory Response; innovation; Laboratories; Length; Maintenance; Mechanics; Medical; Medical Care Costs; Medical center; Methods; Modeling; Natural regeneration; new growth; Newborn Infant; novel; Operative Surgical Procedures; Oral cavity; Patients; Penetration; Perforation; Phase; preclinical study; Preparation; Procedures; Process; repaired; response; Safety; scaffold; Seed Implantation; Small Business Innovation Research Grant; Stem cells; Stomach; Stretching; Techniques; Testing; Thick; Time; Tissue Engineering; Tissues; Travel; Work

Esophageal Atresia (EA) is a congenital birth defect characterized by a discontinuity of the esophagus. Each year several thousand children are born within the EA spectrum. Babies born with EA have trouble feeding, and require a procedure to correct the abnormality. The best treatment for EA is surgery reconnecting the two ends of the esophagus to each other. In some children, however, the gap between the two esophageal ends is too long to be easily connected. This condition is known as long-gap esophageal atresia (LGEA). Current surgical options available for the treatment of LGEA focus upon either the replacement of the esophageal tissue with other autologous tissue, or mechanically stretching the current esophageal tissue to bridge the gap. Although there are several techniques available, there is little consensus about the optimal repair of LGEA. In addition, the infrequent occurrence of LGEA also means that development of improved techniques is greatly hampered. Thus, there is clearly an unmet clinical need for effective methods of esophageal repair. To answer this unmet medical need, Biostage Inc and our academic partners at Connecticut Children’s Medical Center (CT Children’s) propose to develop a novel tissue-engineered esophageal implant that combines a synthetic scaffold with patient derived stem cells, as a treatment for LGEA. Biostage's Cellspan Esophageal Implant has the unique ability to induce the body's own repair mechanism, while providing spatial cues to assist regeneration. Previous preclinical studies at Biostage have established that full-thickness circumferential esophageal defects can be treated by implanting the CEI in an adult pig model. Studies at the Finck laboratory have shown that autologous epithelial cell seeded scaffold can be utilized to treat similar defects in a piglet model. Based on these findings we plan to develop a novel tissue engineered esophageal implant to address LGEA in newborns. The goal of the project will be establishing long-term efficacy of our CEI as an esophageal replacement in piglet pediatric model. Phase I will include the preparation of CEI with size relevant for a pediatric model (Specific Aim #1). We will create a CEI by seeding piglet cells on 3D scaffold in bioreactor and analyze the CEI to determine cell viability, cell penetration and cell functionality in terms of MSC marker expression and cytokine secretion profiles. In Phase II we will perform a short-term in vivo feasibility study of CEI as an esophageal replacement in a piglet model (Specific Aim #2). Once we confirm that no acute adverse effects arise due to animal exposure to the CEI, we will conduct a long term in vivo study (Specific Aim #3), where we will follow the growth and development of the tissue in the implant zone. The ability of the animals to function normally at such longer time scales will be key to assess the use of the CEI as an esophageal treatment. Upon completion of these Aims, we will initiate dialogue with the FDA to obtain pre-IND guidance and will carry out pre-clinical studies to ensure a clinical path for the use of CEIs as a treatment for pediatric atresia.

Public Health Relevance Statement:
long-gap esophageal atresia (LGEA) is a congenital birth defect characterized by a discontinuity of the esophagus, where the gap between the two esophageal ends is too long to be easily connected.There is little consensus about the optimal repair of LGEA and its infrequent occurrence means that development of improved techniques is greatly hampered. In this Fast-Track SBIR application Biostage is seeking to develop a retrievable autologous bioengineered esophageal implant, as a novel treatment for long-gap esophageal atresia.

Project Terms:
3-Dimensional; Acute; Address; Adipose tissue; Adult; Adverse effects; Affect; AlamarBlue; angiogenesis; Animal Model; Animals; Autologous; base; Biological Assay; Biomedical Engineering; Bioreactors; Cell Adhesion; Cell physiology; Cell surface; Cell Survival; Cells; Child; Childhood; Clinical; Clinical Paths; Congenital Abnormality; Connecticut; Consensus; Cues; cytokine; Defect; design; Development; Engineering; Ensure; Enzyme-Linked Immunosorbent Assay; Epithelial; Epithelial Cells; Esophageal; Esophageal Atresia; Esophageal Diseases; Esophageal Tissue; Esophagus; Event; Excision; Exposure to; Family; Family suidae; Feasibility Studies; feeding; Flow Cytometry; Food; Future; Glucose; Goals; Growth; Growth and Development function; Healthcare Systems; Histologic; Implant; implantation; improved; in vivo; in vivo evaluation; Individual; Inflammation; Inflammatory Response; innovation; Laboratories; Length; Maintenance; Mechanics; Medical; Medical Care Costs; Medical center; Methods; Modeling; Natural regeneration; new growth; Newborn Infant; novel; Operative Surgical Procedures; Oral cavity; Patients; Penetration; Perforation; Phase; preclinical study; Preparation; Procedures; Process; repaired; response; Safety; scaffold; Seed Implantation; Small Business Innovation Research Grant; Stem cells; Stomach; Stretching; Techniques; Testing; Thick; Time; Tissue Engineering; Tissues; Travel; Work