SBIR-STTR Award

The role of proteoglycans and carbohydrate polymers such as heparan sulfate in biological processes are becoming better understood, but this new frontier has only begun to be explored. Tissue regeneration is also an emerging frontier. This proposed research, when completed, will make an important contribution to both the proteoglycan and tissue regenerative fields, with a specific, clinical impact on periodontal regeneration. Perlecan, originally named heparan sulfate proteoglycan-2, is now known to be an important component of all basement membranes (along with collagen type IV and laminin). There is strong scientific support and rationale for a role of heparan sulfate-decorated Perlecan in angiogenesis or neovascularization. The heparan sulfate of Perlecan is reported to promote cell adhesion, to promote proliferation and/or differentiation, and to bind and deliver growth factors. Expression of a heparan sulfate-decorated recombinant Perlecan D1 (rD1) in a variety of cell types has since been validated. The rD1 was shown to bind fibroblast growth factor and promoted cell adherence in vitro. In periodontal regeneration, barrier membranes are an important adjunct to procedures aimed at restoring the form and function of the mouth. During these guided tissue regenerative (GTR) procedures, barrier membranes are positioned between the surgical flap and the underlying regenerative site. Nevertheless, an unnecessarily high failure rate exists in GTR procedures due to failure of the flaps to heal with primary closure over the membranes and regenerative site, typically leading to exposure of the regenerative site to the oral environment. The objectives of this Phase I application are 1) to determine an effective manner of loading commonly used barrier membranes with Perlecan domain 1 expression constructs within clinically acceptable parameters, 2) to compare in vitro cellular expression of, and cellular responses to, the Perlecan domain 1 construct generated by membranes loaded with the Perlecan D1 transgene delivery system vs. the sham-loaded membranes, and 3) to compare in vivo responses generated by placement of the loaded vs. the sham-loaded surgical membranes in an animal model for healing by 2¿ intention. Membranes will be pre-treated by parameters established in vitro then secured beneath a gingival flap with a defined area of membrane exposure. Healing will be measured clinically and histologically where rate of exposed membrane coverage by epithelium will be the primary outcome. The well-supported rationale for heparan sulfate and Perlecan D1 delivery to support tissue regeneration, coupled with these preliminary data and Agenta's relevant patent, uniquely positions Agenta to fulfill the objectives of this proposed project.

Project Terms:
Adenoviruses; Adherence (attribute); angiogenesis; Animal Model; Area; Basement membrane; Binding (Molecular Function); Biological Process; Blood Vessels; Bos taurus; Carbohydrates; Cattle; Cell Adhesion; Cell Proliferation; cell type; Cells; Clinical; Closure; Collagen Type I; Collagen Type IV; Condition; Coupled; Data; Development; Differentiation and Growth; Endothelial Cells; Environment; Epithelial Cells; Epithelium; Evaluation; Exposure to; Failure (biologic function); Fibroblast Growth Factor; Fibroblasts; frontier; Gingiva; Goretex; Growth Factor; Guided Tissue Regeneration; Guidor; Healed; healing; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Histologic; Imaging Device; In Vitro; in vivo; Inflammation; Intention; Kinetics; Laboratories; Laminin; Legal patent; Measures; Membrane; Modeling; Molecular; Names; Natural regeneration; neovascularization; Operative Surgical Procedures; Oral; Oral cavity; Outcome; particle; perlecan; Phase; Placement; Polymers; Polytetrafluoroethylene; Positioning Attribute; Procedures; Promotor (Genetics); Proteoglycan; Rate; Rattus; Recombinants; Reporting; Research; research study; response; Role; Secure; Site; success; Surgical Flaps; System; Testing; Time; Tissue membrane; tissue regeneration; Tissues; transgene expression; Transgenes; uptake; wound

Barrier membranes are an important adjunct to regeneration therapy aimed at restoring the form and function of the mouth. Commercially available barrier membranes are used in dental surgeries to help retain bone grafting materials, to help exclude epithelium and connective tissue from entering into sites of desired bone and ligament regeneration, or for the combination of these reasons. Whether restoring lost bone around teeth or implants, or in larger areas of the jaws affected by trauma or disease, too often there is inadequate gum tissue to cover the membranes which can lead to membrane exposure, extensive membrane contamination, and procedural failure which is unacceptable. Our data suggests that biologically activating membranes made of chitosan (a versatile, biocompatible, resorbable material used in wound bandages) with our proprietary biologic - a small and soluble heparan sulfate-rich co-activator of growth factors - hastens gingival healing over exposed membranes in the mouth. R&D for this project is directed at development of a bioactivated chitosan regenerative membrane that is highly effective in maintaining gingival health and integrity where membranes are unavoidably exposed to the oral environment after placement, thereby promoting more predictable outcomes for a wider range of regenerative procedures in the mouth. R&D for this project falls along three lines: biologic development, membrane development, and in vivo testing. More specifically, we will 1) advance the prototype biologic used in phase 1 studies, 2) advance our chitosan membrane formulations to incorporate bioactivation with the most clinically appropriate handling characteristics, and 3) test the product candidates in animal models for efficacy. Toxicology and safety testing will be performed with the goal of having product candidate(s) ready for human clinical trials by the end of this phase 2 project. We expect this technology to improve success rates of oral bone regenerative procedures to treat periodontal disease, to place dental implants, and in cases where maxillofacial reconstruction is needed, therefore meeting patient needs and commercial needs in a large market. There is an absence in today's standard of care for bioactivated regenerative membranes and this proposed technology addresses that need with a rationally designed R&D plan with an understanding of the existing market, competitors, or potential partners.

Public Health Relevance:
Agenta is developing biologically enhanced regenerative membranes that are used in surgical procedures such as bone grafting. Bone regeneration is often necessary and critical to successful restoration of form and function in the mouth, and procedures called guided tissue regeneration using barrier membranes are essential to achieving optimal results. Whether restoring lost bone around teeth or implants, or in larger areas of the jaws affected by trauma or disease, too often there is inadequate gum tissue to cover the membranes and the graft sites which can lead to membrane exposure and procedural failure. Our data suggests that augmenting membranes made of chitosan (an excellent biodegradable material used in wound bandages) with our proprietary biologic improves gingival healing over exposed membranes in the mouth. Chitosan is a versatile, biocompatible, resorbable matrix with hemostatic and antimicrobial properties. Our goal is to provide chitosan with the additional biological advantage of enhancing wound closure with our proposed technology. We expect this technology to improve success rates of oral bone regenerative procedures to treat periodontal disease, to place dental implants, and in cases where maxillofacial reconstruction is needed, therefore meeting patient needs and commercial needs in a large market. There is an absence in today's standard of care for bioactivated regenerative membranes and this proposed technology addresses that need with a rationally designed R&D plan with an understanding of the existing market, competitors, or potential partners.

Public Health Relevance Statement:
Agenta is developing biologically enhanced regenerative membranes that are used in surgical procedures such as bone grafting. Bone regeneration is often necessary and critical to successful restoration of form and function in the mouth, and procedures called guided tissue regeneration using barrier membranes are essential to achieving optimal results. Whether restoring lost bone around teeth or implants, or in larger areas of the jaws affected by trauma or disease, too often there is inadequate gum tissue to cover the membranes and the graft sites which can lead to membrane exposure and procedural failure. Our data suggests that augmenting membranes made of chitosan (an excellent biodegradable material used in wound bandages) with our proprietary biologic improves gingival healing over exposed membranes in the mouth. Chitosan is a versatile, biocompatible, resorbable matrix with hemostatic and antimicrobial properties. Our goal is to provide chitosan with the additional biological advantage of enhancing wound closure with our proposed technology. We expect this technology to improve success rates of oral bone regenerative procedures to treat periodontal disease, to place dental implants, and in cases where maxillofacial reconstruction is needed, therefore meeting patient needs and commercial needs in a large market. There is an absence in today's standard of care for bioactivated regenerative membranes and this proposed technology addresses that need with a rationally designed R&D plan with an understanding of the existing market, competitors, or potential partners.

NIH Spending Category:
Bioengineering; Dental/Oral and Craniofacial Disease; Regenerative Medicine

Project Terms:
Address; Adenoviruses; Affect; Agreement; Animal Model; Animals; antimicrobial; Area; Bandage; Biocompatible; Biocompatible Materials; Biologic Development; Biological; Biopsy; Biotechnology; bone; Bone Regeneration; Bone Transplantation; Characteristics; Chitosan; Clinical; clinical application; Clinical Data; Clinical Trials; Clinical Trials Design; clinically relevant; Colorado; Communities; Connective Tissue; Consult; Data; Dental Implants; dental surgery; design; Development; Development Plans; Devices; Disclosure; Disease; Drug Formulations; Engineering; Environment; Epithelium; Event; Failure (biologic function); falls; Family suidae; Fibroblast Growth Factor; Fibroblast Growth Factor 2; Gingiva; Goals; Growth Factor; Guided Tissue Regeneration; Healed; healing; Health; Hemostatic Agents; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Human; Human Resources; Implant; improved; In Situ; in vitro Assay; in vivo; Industry; industry partner; Inflammation; innovation; Jaw; Laboratories; Lead; Licensing; Ligaments; Liposomes; Marketing; maxillofacial; Measurement; Measures; meetings; Membrane; migration; Modeling; Modification; Molecular; Natural regeneration; Operative Surgical Procedures; Oral; Oral cavity; orofacial; Outcome; Pathology; Patients; Performance; Periodontal Diseases; perlecan; Phase; Phase I Clinical Trials; physical property; Plasmids; Preparation; Procedures; product development; Property; prototype; public health relevance; Rattus; Recombinant Fusion Proteins; Recombinants; reconstruction; regenerative; Reporting; research and development; research study; response; restoration; Rivers; Role; Safety; safety testing; Series; Shear Strength; Site; Staining method; Stains; standard of care; success; Surgical sutures; Techniques; Technology; Tensile Strength; Testing; Therapeutic; Thick; Time; Tissues; Tooth structure; Toxic effect; Toxicology; Transgenes; Transplanted tissue; Trauma; user-friendly; Vertebrates; Virginia; Work; wound; Wound Healing