SBIR-STTR Award

On its own, the human body is incapable of dermis regeneration. If not properly treated, large full-thickness skin wounds (loss of dermis) heal through contraction of surrounding skin and scar formation, which may ultimately lead to chronic wound formation, permanent damage, disability, disfigurement and patient suffering. For years, the autologous tissue transfer (a patient serving as their own donor) has been the gold-standard treatment for this type of wound, but lack of surgical expertise, poor donor site availability and significant donor-site morbidity severely limit its application. In the early 2000s, alternative, “off the shelf” neo-dermis formation treatments emerged, which now have annual sales between $500 million to $1 billion, growing 8- 12% annually. The leading product by sales, Integra™, possesses shortcomings in its time to heal and is ineffective in many types of full thickness wound scenarios. DermiSphere™, the proposed product of this SBIR Phase I application will be an implantable scaffold that rapidly restores patients’ functional dermis. DermiSphere’s patented three-dimensional microscopically patterned architecture guides rapid cell penetration from the wound bed into the scaffold matrix, leading to rapid vascularization and neo-dermal tissue formation. Our murine studies to date demonstrate DermiSphere’s superior invasion and neovascularization versus Integra. The collective long-term goal of our SBIR Phase I proposal and contemplated Phase II study is a DermiSphere prototype, ready for clinical trial, that triggers rapid dermal regeneration while avoiding skin contraction and scarring. When compared to currently available dermal substitutes, DermiSphere will induce faster wound closure, form more functional tissue, and lessen required procedures, reducing patient suffering and materially reducing health care cost. In this Phase I study we will prove the feasibility of our product by completing the following Specific Aims: (1) Demonstrate DermiSphere biocompatibility by testing its potential cytotoxicity in vitro by elution method, when formulated using bovine collagen. Criteria for Success: Biological response to DermiSphere is less than or equal to slight reactivity. (2) Demonstrate DermiSphere’s ability to support rapid dermal regeneration in a pilot in vivo swine full-thickness excisional wound model. Criteria for Success: Epidermal take ?75% on day 21 of the study and wound contraction ?20% and ?30% on days 14 and 60 of the study respectively. Our Phase II study will be a full- scale, full thickness excisional swine wound model to validate DermiSphere’s efficacy over Integra. Data from this study will also be used to improve formulation for both scale manufacturing and for pre-clinical safety and efficacy testing requirements. Demonstrating DermiSphere’s superior efficacy over Integra in a full-scale wound model is currently our first major strategic milestone. Achieving this milestone will sufficiently increase the equity value of FesariusTherapeutics Inc. to attract the capital needed to scale operations for increased manufacturing, FDA submission and commercialization.

Public Health Relevance Statement:
PROJECT NARRATIVE Large full-thickness skin loss remains a reconstructive challenge especially when an autograft is not available or desirable. When not properly treated, such wounds heal through contraction of the surrounding skin and scar formation, which may ultimately lead to chronic wound formation, permanent damage and/or disfigurement and as a result – patient suffering. Current treatment approaches including engineered “off the shelf products” have significant limitations, including slow and inadequate tissue formation, hence impaired wound healing. The proposed study will evaluate FesariusTherapeutics novel micropatterned hydrogel technology DermiSphereTM to trigger rapid host cell invasion, scaffold incorporation and dermal regeneration while minimizing skin contraction and scarring.

Project Terms:
3-Dimensional; alternative treatment; animal efficacy; Animals; Architecture; Autologous; Autologous Transplantation; Back; base; Beds; Biological; biomaterial compatibility; Blood Vessels; Cadaver; Capital; Care given by nurses; Cattle; cell motility; Cells; Child; chronic wound; Cicatrix; Clinical Trials; Collagen; commercial application; commercialization; Contracture; cost; Cues; cytotoxicity; Data; density; Dermal; Dermis; Devices; Dimensions; disability; efficacy testing; Engineering; Excision; Family suidae; flexibility; Formulation; Goals; Gold; Growth; healing; Health Care Costs; Human body; Hydrogels; Immobilization; immunogenicity; Impaired wound healing; Implant; implantable device; improved; In Vitro; in vivo; Infiltration; Injury; Knowledge; Lead; Legal patent; Medical Device; medical schools; Methods; Microscopic; Microspheres; Modeling; Morbidity - disease rate; Mus; Natural regeneration; neovascularization; novel; off-patent; operation; Operative Surgical Procedures; Patients; Pattern; Penetration; Phase; phase 1 study; phase 2 study; Pilot Projects; preclinical efficacy; preclinical safety; Preclinical Testing; prevent; Procedures; Process; prototype; Rattus; reconstruction; Reconstructive Surgical Procedures; Research; response; Safety; safety testing; Sales; scaffold; Site; Skin; Skin graft; Skin Tissue; Skin wound; Small Business Innovation Research Grant; standard care; subcutaneous; success; Tail; Technology; Tendon structure; Testing; Thick; Thinness; Time; Tissues; Vascularization; wound; wound closure; Wound Healing

On its own, the human body is incapable of dermis regeneration. If not properly treated, large full-thickness skin wounds (loss of epidermis and dermis) heal through contraction of surrounding skin and scar formation, which may ultimately lead to chronic wounds, permanent damage, disfigurement and patient suffering. For years, the gold-standard treatment has been autologous tissue transfer (a patient serving as their own donor), but insufficient donor site availability, secondary contracture of split thickness skin grafts and major donor-site morbidity leaves surgeons wanting alternatives. In the early 2000's, engineered treatments emerged, which now have annual sales from $500MM to $1BN, growing 8-12% annually. The market leader, Integra™, has several shortcomings in both the rate and degree of healing as well as decreased effectiveness in challenging wounds. DermiSphere™, the proposed product of this application is an implantable dermal regenerative scaffold that addresses these concerns. DermiSphere's (DS) patented 3D patterned microarchitecture guides rapid cell penetration from the wound bed into the scaffold, leading to swift vascularization and neo-dermis formation. Our previous studies treated clinically-relevant rodent and pig wounds with a DS prototype, and demonstrated improved performance as compared to Integra (>75% graft take vs. ~50% respectively), decreased hemorrhage, enhanced graft vitality and a 40% increase in dermal thickness. These all indicate better clinical outcomes. Completion of this Phase II proposal will result in a frozen DS design that will then be used in biocompatibility and validation testing as required for FDA 510(k) clearance. Furthermore, this frozen design will be validated for superior performance versus Integra in a clinically relevant pig full-thickness wound model. Specifically, the study will evaluate the value proposition determined during the NIH iCorps program of ?20% improvement in graft “take” time/incidence and wound contracture vs. Integra. In Phase II, we will complete two Specific Aims 1: Design Freeze for the optimized DS. DS is two layers: a polysiloxane (silicone) layer and a type I collagen scaffold (comprised of bulk collagen and embedded collagen microspheres). This aim contains four tasks to develop the “final” version of the device meant for commercial use: (1) & (2) Optimize microsphere size and crosslinking and bulk collagen using cGMP compliant collagen sources and equipment; (3) Optimize the occlusive layer for clinical use; (4) Develop terminal sterilization parameters without adversely affecting DS. The resulting prototypes will be screened for efficacy using a rat full-thickness wound model. 2: Demonstrate superiority to the market leader and meet/exceed our performance value proposition in the clinically-relevant, full-thickness excisional model in swine. An optimized DS with a frozen design that has superior efficacy over Integra in a full-scale (porcine) wound model is currently the first major strategic milestone. This will sufficiently increase the equity value of FesariusTherapeutics Inc. to attract the capital needed to scale operations for cGMP manufacturing, FDA submission and commercialization.

Public Health Relevance Statement:
PROJECT NARRATIVE When autologous tissue is not available or split thickness skin grafts alone are used, full-thickness skin loss may not heal or will heal by contracture of the surrounding skin resulting in unstable healed wounds that do not contain the normal epidermal/dermal architecture of healthy skin, but rather significant scar tissue formation that results in substantial functional and aesthetic impairment for the patient. Current treatment approaches including engineered “off the shelf products” have significant limitations, including slow, inconsistent, and inadequate tissue formation, hence impaired wound healing. The commercialization of DermiSphereTM is expected to improve clinical practice in surgical fields where full thickness skin loss is common including, but not limited to, trauma, burns, and post oncologic reconstructive surgery, by significantly decreasing the time required to achieve a healed wound, as well as increasing the thickness of the regenerated dermis in a scenario of (large) full thickness skin loss

Project Terms:
3-Dimensional; Address; Affect; alternative treatment; animal tissue; Animals; Architecture; Autologous; base; biomaterial compatibility; Blood Vessels; Burn injury; Capital; Carbon Dioxide; Care given by nurses; Cattle; cell motility; Cells; chronic wound; Cicatrix; Clinical; clinical practice; clinically relevant; Collagen; Collagen Type I; commercialization; Complication; Contracture; crosslink; Cues; Cyclic GMP; density; Dermal; Dermis; design; Development; Devices; Effectiveness; Electron Beam; Engineering; Epidermis; Epithelial; Epithelium; Equipment; Esthetics; Excision; Family suidae; flexibility; Formulation; Freezing; Goals; Gold; Group Processes; healing; Hemorrhage; Human; Human body; human tissue; Hydrogels; Immobilization; immunogenicity; Impaired wound healing; Impairment; Implant; implantation; improved; Incidence; infection risk; Infiltration; Knowledge; Lead; Legal patent; Membrane; Microfluidics; Microspheres; Modeling; Morbidity - disease rate; Natural regeneration; operation; Operative Surgical Procedures; Outcome; Patients; Pattern; Penetration; Performance; Phase; Pliability; prevent; Procedures; Process; programs; prototype; Rattus; Reconstructive Surgical Procedures; regenerative; release factor; Rodent; Sales; scaffold; screening; Silicones; Siloxanes; Site; Skin; Skin graft; Skin Tissue; skin wound; Small Business Innovation Research Grant; Source; standard care; Sterilization; Surgeon; Tendon structure; Testing; Thick; Thinness; Time; Tissues; Transplantation; Trauma; United States National Institutes of Health; Validation; Vascularization; water vapor; wound; wound bed; wound healing; Wound models