Regenerative Medicine Resource Center - 2023 Annual Report by M Dentistry

2023

Annual Report

Letter from the Leadership It is with great gratitude that we welcome the 7th year of operations of the Michigan-Pittsburgh-Wyss Regenerative Medicine Resource Center. Within these pages, we share the achievements of the Resource Center and each of the Interdisciplinary Translational Projects. Our partners’ unwavering support and guidance, coupled with the commitment of our project teams, have been the driving force behind these remarkable accomplishments. This report stands as a testament to our shared, steadfast dedication to advance innovative solutions that hold the promise of improving dental, oral, and craniofacial healthcare outcomes and enhancing quality of life. Thank you for your continued support of the Michigan-Pittsburgh-Wyss Regenerative Medicine Resource Center. David H. Kohn, PhD | University of Michigan William V. Giannobile, DDS, DMSc | Harvard University David J. Mooney, PhD | Wyss Institute Charles S. Sfeir, DDS, PhD | University of Pittsburgh William R. Wagner, PhD | University of Pittsburgh

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About the MPWRM Resource Center The Michigan-Pittsburgh-Wyss Regenerative Medicine (MPWRM) Resource Center is one of the two national Resource Centers established by the National Institute of Dental and Craniofacial Research (NIDCR)’s Dental Oral and Craniofacial Tissue Regeneration Consortium (DOCTRC) initiative,

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under award numbers U24DE026915 & U24DE029462. With the overarching goal of developing clinical trial-ready tissue engineering/ regenerative medicine products and protocols, the DOCTRC initiative provides funding and resources through the Interdisciplinary Translational Project (ITP) program administered by the two national Resource Centers. The MPWRM Resource Center brings together a multidisciplinary team of clinicians, engineers, scientists, and technology commercialization and regulatory experts from

2 | 3 | 4 | 6 | 8 | 50 |

Letter from the Leadership About the MPWRM Resource Center MPWRM Resource Center Impact | ITP Program by Numbers Year in Review MPWRM Resource Center ITP Portfolio Building Partnerships

academia and industry. This team supports the regenerative medicine research community by providing resources and expertise to guide innovations that address unmet clinical needs for the regeneration or restoration of DOC tissues. Through its Core Services and Resources, the MPWRM Resource Center strives to accelerate the translation of promising technologies towards clinical trials and beyond.

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MPWRM Resource Center Impact ITP Program by Numbers The Interdisciplinary Translational Project (ITP) program seeks to identify promising technologies that address clear unmet clinical need with market potential in the dental, oral, and craniofacial (DOC) space, and to catalyze the clinical translation of these technologies towards FDA submissions. The long-term goal is to achieve high-impact outcomes in the clinical marketplace. To date, we have reviewed over 100 projects from around the world.

Montreal Quebec, Canada

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Sao Paolo Sao Paolo, Brazil

The MPWRM Resource Center consists of more than 60 members whose expertise spans the spectrum of translational research and commercialization. With the majority of the members serving on an ITP Advisory Team, each project receives broad and customized guidance.

INSTITUTION TYPE (N=11)

Our mission is to strategically partner with scientists, engineers, and clinicians in the public and private sectors to translate dental, oral, and craniofacial tissue engineering and regenerative medicine technologies to the clinical marketplace.

External: for-profit

109 22 11 Total number of projects reviewed

Total number of projects funded to date

Total number of currently active projects

External Internal

TECHNOLOGY TYPE

ITP TEAMS WITH: Issued or pending patent/applications

FDA interactions

91% 82%

Total number of follow-on grants and award recognitions

>43

Device

Combination

Biologic

Total amount of follow-on funding (including grants and fundraising activities)

>$39M

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TISSUES ADDRESSED

Bone

Tooth

Periodontal

Dental Implant

Nerve

Salivary Gland

Skin

Year in Review 2022 | Q4

2023 | Q1

• ITP team, RevBio, awarded SBIR for vertebral fracture indication, receives approval to start a clinical trial in the UK for dental implant stabilization

• ITP team, GreenMark Biomedical, wins pitch event @ Yankee Dental and launches CrystLCare™ Biorestorative, Fluoride-Free

• DOCTRC co-hosts AADOCR Fall Focused Symposium, Accelerating Translation of Tissue Engineering and Regenerative Medicine Technologies in the Dental, Oral, and Craniofacial Space • 3rd Annual DOCTRC Retreat in Ann Arbor, MI

• RevBio, receives a strategic investment from Pacific Dental Services, approval to start a clinical trial in Italy for mandibular and maxillary dental arch bone regeneration • ITP PI, Pamela Yelick, named Fellow of the AAAS

• RevBio’s Bone Adhesive Flies on SpaceX CRS-26

• Work led by ITP PI, Luiz Bertassoni, featured on Oregon Public Broadcasting

• Request for Proposals close for the ITP Program, Cycle 8

• DOCTRC presents @ 2023 AADOCR Annual Meeting in Portland, Oregon

• ITP team, Amend Surgical, receives patent notice of allowance

• 2023 MPWRM Resource Center Annual Stakeholder’s Summit in Pittsburgh, PA

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2023 | Q2

2023 | Q3

• GreenMark’s CrystLCare™ featured on Dental Products Report, first third-party clinical study for LumiCare™ published

• MPWRM Resource Center and DOCTRC highlighted in keynote talk at NIDCR’s 75th Anniversary

• New project joins the ITP program: Suture-less Trigeminal Nerve Repair Device (Amend Surgical) • DOCTRC presents @ IADR 2023 in Bogota, Columbia • RevBio, awarded Phase II SBIR from NIDCR for dental bone grafting indication

• Project from Isabelle Lombaert, ITP PI, selected for Frankel Innovation Initiative Fund • Resource Center PI, William Giannobile, on new Legends of Oral Regeneration Podcast • Resource Center PI, David Kohn, named BMES Fellow • ITP Team, Ostiio awarded Phase II SBIR from NIDCR • 4 ITPs selected to present @ 2023 Forsyth dentech pitch competition: Amend Surgical, GreenMark Biomedical, RegendoDent (2nd place), RevBio (1st place)

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Amend Surgical - Innovations that Enhance Oral Wound Healing and Regeneration Amend Surgical (Amend) began its journey into the DOC space after securing an exclusive license for a very promising new technology developed at the Wyss Institute at Harvard University (Wyss). The license was focused on oral maxillofacial indications and finalized in 2020 (6 issued patents, 6 pending).The technology Amend licensed was developed to address the general medical need for strong adhesives that work over long periods of time in moist, mechanically demanding environments. Wyss used sophisticated chemistry - inspired by the tough and sticky mucus of the Dusky Arian Slug - to develop a biocompatible hydrogel and surgical glue that adheres to and protects wounds for weeks on wet, uneven surfaces, such as those found in the oral cavity.

The first product development effort Amend asked the MPWRM Resource Center (RC) to support was in 2021, with an initial focus on a non-resorbable tissue tape that can be used as an oral wound care “overlay” in multiple indications. Since successful wound closure and stable healing is key to predictable outcomes with most oral regenerative procedures, Amend Tissue Tape has the potential to directly impact the success of many of the soft and hard tissue regenerative treatments being performed today, and that the RC seeks to advance.

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The technology Amend licensed from Wyss has the potential to be further differentiated as a resorbable “inlay” barrier used under tissue flaps to increase predictability and improve ease-of-use and outcomes in several DOC regenerative indications. Recently the company has also started to develop it as an oral nerve “wrap” to replace sutures and/or bridge gaps. In the future, this robust platform technology could also be loaded with drugs or biologics as a delivery vehicle to further enhance regenerative outcomes in especially challenging indications, or

knew how to raise capital and operate out of clean rooms under cGMP, FDA and state regulated processes. In addition, they had recently hired a dedicated engineer and technical leader, Jamie Shaikoski, to focus on advancing this very promising DOC technology. The first thing Amend needed from the RC was a market assessment to confirm their assumptions about where this technology would have clinical value in the DOC space. They understood that their entire development program would be impacted by selecting the “right” indications. Through a series of in-depth interviews organized by the RC with key opinion leaders in this space, Amend got positive feedback but was quick to pivot to the indications where the clinical need and value was greatest.

improve efficacy in many situations where local, more targeted delivery is desired. This tremendous potential to significantly impact oral regenerative procedures and improve human health made Amend a strong candidate for RC support. This was especially true because they knew that they needed help and were clearly motived to tap into the expertise at the RC, beginning in the seed funding phase. When Amend first approached the RC, they already had an existing small business with expertise in contract manufacturing for an orthopedic bone graft substitute they had been producing since 2015. They also had a strong business leader (Robby Lane) who

In addition to tapping into the RC’s market knowledge, Amend benefited from multiple introductions to key potential partners and investors in the oral regenerative industry. They also valued the RC’s ability to provide technical and regulatory support, with a critical role in determining the best sterilization method for this new technology, which will be key to a successful FDA submission. Since the product value “in use” is related to how it handles, they also took advantage of the RC’s ability to organize surgical handling sessions with experienced clinicians who provided feedback on everything from technique to packaging, pricing, preferred configurations and even some brand elements the RC helped them develop. In general, Amend has worked closely with the RC to demonstrate efficacy to the FDA and engage clinicians who will drive clinical adoption. The hope was that by working with the RC, Amend could significantly de-risk and fast track this promising new technology. This hope has been realized every step of the way with pre-clinicals and a successful FDA pre-submission meeting initiated in 2022. Based on the feedback they received, FDA clearance for the first indication as a non-resorbable oral wound dressing over periods of <24 hours is expected by Q1 2024. Preparations for the second 510(k) to allow for longer adhesion periods are already underway. In addition, the resorbable

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The Market Assessment Core has been critical to Amend’s understanding of dental markets and connections with KOLs. They continue to provide significant input and have been vital for the commercialization of Amend Tissue Tape TM. product (Amend Tissure) for barrier “inlay” indications will be ready for pre-clinical development by 2024. In addition to the funding in 2021-2022 for development of Tissue Tape, Amend was recently awarded additional support by the RC to develop Tissure as a nerve “wrap” to avoid sutures and/or bridge gaps, with an initial focus on the trigeminal nerve in the oral and craniofacial space. This study and FDA submission will allow for general use of this technology in nerve indications, so even more patients can benefit. By initially helping the company develop an FDA strategy and clinical value proposition for Amend Tissue Tape, the RC is now able to support expansion of this technology platform into other indications – such as resorbable “inlay” barriers and nerve “wraps” - in the DOC space… and beyond. Amend Surgical has made significant progress with support from the generous NIDCR grant that the RC has been charged with administering, shepherding them through (and over) the “Valley of Death” to clinical adoption and improved human health. Investors and potential industry partners are showing serious interest in working with Amend in the DOC space. Patients will be the ultimate beneficiaries. This is one of many success stories we are proud to share! 9

Amend Tissue Tape™ for Oral Wound Care Clinical Need An intraoral wound overlay for soft tissue that is easy to apply, remains in place for the duration of wound healing, and can be removed without causing damage to underlying tissue. Current options for oral wound care are limited to difficult to use, uncomfortable, and largely ineffective glues and resins.

Solution Amend Tissue Tape™ is a hydrogel-based adhesive comprised of two primary elements. The hydrogel consists of an interpenetrating network of alginate and polyacrylamide. The adhesive is composed of chitosan, which forms covalent bonds across the interface. When used together, the hydrogel and adhesive adhere to wet tissue and provide over five times the adhesion energy of cyanoacrylate while also providing a long duration mechanical barrier for the wound and flexibility to stretch with the wound without damaging the underlying tissue.

Competitive Advantage There are limited products available that will safely adhere to sutured or nonsutured oral wounds. Periacryl, a cyanoacrylate-based product indicated as a dental cement, is often used off-label for wound closure. It requires a dry environment to fully set and is rigid, not stretching to accommodate movement or swelling. Amend Tissue Tape™ adheres to tissue in a wet environment, stretches with the wound, and stays in place for weeks, allowing wound healing to occur.

Foundational Publications & Patents • Li et al. Tough adhesives for diverse wet surfaces. Science 2017 • PCT/US2019/055779 Bio-Inspired Degradable Tough Adhesives for Diverse Wet Environments

Jamie Shaikoski, PhD Amend Surgical

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ITP Support • Upon entry to the ITP program in 2021, optimization and initial demonstration of safety and efficacy of Amend Tissue Tape was performed. • In the current ITP project stage in 2023, advanced characterization, initiation of manufacturing, and regulatory submission will be completed by the end of the grant period.

Key Inflection Points/ Regulatory Pathway • 510(k) to be filed Q1/2024 • Upon FDA clearance, a post-market multisite clinical study will be initiated • Initiate GMP production • Perform non-GLP animal studies to assess adhesion performance on different tissue types • Compile documents for 510(k) submission, submit 510(k), and obtain FDA clearance

Opportunities for Partnerships • Pursue OEM partner • Engage with commercial partner • Initiate Series A equity financing round

Michigan-Pittsburgh-Wyss Regenerative Medicine Resource Center is supported in part by the National Institute of Dental & Craniofacial Research of the National Institutes of Health under Award Number U24DE029462. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Suture-less Trigeminal Repair Device Clinical Need Micro-suturing is the current standard of care for the repair of trigeminal nerve injuries. Micro-sutured repairs are technically challenging and often inconsistent, with flaws in both fascicular alignment and spacing between severed nerve ends. Scar tissue associated with suture placement can impede axonal regeneration. Clinical need for oral surgeons: a suture-less repair solution.

Solution Tissure™ is a degradable, hydrogel and chitosan-based nerve connector that has the adhesion and mechanical strength required to eliminate the need for suture to reconnect peripheral nerves. The product adheres to wet nerve tissue and provides over five times the adhesion energy of cyanoacrylate while also providing flexibility to stretch through range of motion without damaging nerve healing.

Competitive Advantage Current competitors in peripheral nerve repair offer largely undifferentiated collagen and polymer materials for connectors, conduits, and wraps. None of the competitors offer a suture-less alternative for a direct (non-connector) nerve repair and all of their product lines require suture to prevent migration of their product.

Foundational Publications & Patents • Wu DT et al. Tough adhesive hydrogel for intraoral adhesion and drug delivery. J Dent Res 2023 • Freedman, B et al. Degradable and removable tough adhesive hydrogels. Adv Mater 2021 • US9,387,276, US10,383,980 Interpenetrating networks with covalent and ionic crosslinks

Robert Lane Amend Surgical

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ITP Support At the time of entry into the ITP program in 2023, the project already had a prototype and initial benchtop testing completed. At the end of the project period, design freeze and a non-GLP animal study are anticipated.

Key Inflection Points/ Regulatory Pathway • 510(k) anticipated; pre-submission meeting will be held in Q2 2024 • Research and planning: market assessment, regulatory opinion and potential corporate partnerships • Determine degradation rate, tune adhesion strength and perform benchtop comparative testing • Perform animal nerve conduction study

Opportunities for Partnerships • Company will initiate a Series A financing in Q4 2023 to support final year of development of Tissure™ • Company is in due diligence with a strategic product development and distribution partner

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Towards a Brighter Future: From Evolution to Revolution in Pediatric Dental Regeneration with Vital-Dent “We are trying to do whatever is possible to save the tooth first.” This comment from a parent of a child with a traumatic dental injury is what drives the team to develop a therapy to revitalize pulp and maintain teeth in children. The hydrogel-based platform technology was originally explored for the regeneration of the bone growth plate over a decade ago in 2012. After exploring various applications for this technology, the team led by Drs. Juan Taboas and Herb Ray at the University of Pittsburgh (Pitt), is now advancing the biomaterial-based therapy to regenerate dental pulp, focusing on the pediatric population. The current project team formally came together in 2017, through a student initiative for an i-Corps program at Pitt. Over the years, more than 12 individuals have worked on the project, advancing it at each step along the way. The project entered the ITP program in 2019, under the leadership of Dr. Taboas, an Associate Professor in the Department of 14

Oral and Craniofacial Sciences and a biomedical scientist with a broad background in bioengineering, and Dr. Ray, former chair of the Department of Endodontics, a highly respected endodontist. Since its entry in the program, the MPWRM Resource Center (RC) has supported the project with the aim of advancing the product to clinicals and enhancing clinical adoption. In collaboration with the Market Assessment Core, the team has conducted several rounds of in-depth interviews with endodontists to test and hone the value proposition of this biomaterial-approach, they call Vital-Dent. Through these conversations, the team came to appreciate that regenerative endodontics is still nascent relative to other dental speWWW.MPWRM-DOCTRC.ORG

cialties where regenerative approaches have been integrated into clinical practice, and decided to focus Vital-Dent’s initial activities on high value indications for the pediatric population. In this subset of the patient population, the current approach is often to stabilize the tooth until more definitive treatment can be performed when the child stops growing. As a result, the whole tooth is not revitalized after pulp removal, leading to tooth discoloration, loss of tooth structure, and limited (if any) tooth growth. With Vital-Dent’s ability to promote pulp revitalization and dentin regeneration, the goal is to attain long-term survival of the natural tooth structure.

The formulation of Vital-Dent has also evolved during its development in the ITP program. With input from the RC experts, the composition has gone through multiple iterations to be able to take advantage of a streamlined pathway for FDA submission. In collaboration with the Regulatory Core, the team is working on design control processes for the development of Vital-Dent, and the MPWRM Resource Center’s Quality Assurance Core conducted a visit with the investigators’ laboratory at Pitt. Together, the team developed a regulatory strategy that anticipates a 510(k) pathway, and roadmap for the submission including studies and partners with whom those studies will be conducted. The team has also leveraged various resources at its home institution. Prior to its engagement with the ITP program, the project was supported by the i-Corps program

The support from and discussions with the Regulatory Core have been critical in defining the mechanism of action, key development steps, and responses to our interested investors.

Core has also been an integral part of the team in its continued advancement on the business front. Working together with the Commercialization Core, the team worked with the home institution to refine its intellectual property strategy. The Core has also supported the team’s engagement with external parties interested in this technology. In addition, with combined support from the Market Assessment Core, the RC has helped the project team prepare a presentation to Renaissance Health Service Corporation that culminated in a $100,000 research grant for the project.

at Pitt, which enabled them to complete an initial customer discovery to explore dental applications of Vital-Dent. Subsequently, pilot studies were also supported by a program within Pitt, which became the basis of the application to the ITP program. Through the ITP program, the RC’s Commercialization

With the roadmap as its guiding light, the Vital-Dent team is striving to create regenerative therapies for children, because they are underserved in tissue engineering and regenerative medicine, with the ultimate goal to save their teeth after traumatic injury and pulpitis.

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Vital-Dent, A Revitalizing Root Canal Implant Clinical Need Approximately 5 million procedures are performed in the USA each year to treat pulpitis of permanent teeth in the pediatric population. Children are often subject to multiple procedures because the standard of care is to stabilize the tooth until more definitive treatment can be performed when the child’s growth stops. The outcomes are unideal, because the whole tooth is not revitalized after pulp removal, resulting in tooth discoloration, loss of tooth structure, and limited (if any) tooth growth.

Solution Vital-Dent is an acellular, resorbable hydrogel scaffold intended for revitalization of tooth pulp and maintenance of tooth vitality in immature permanent teeth treated with endodontic therapies. It is supplied as a powder in a single-use kit with sterile saline. The powder is rehydrated at the chairside using kit tools to make a clear liquid. The liquid is inserted into the instrumented canal space as would conventional sealers and sets in three minutes with a dental curing lamp to form the colorless Vital-Dent hydrogel. The tooth is then sealed with a bioceramic and restored with conventional techniques.

Competitive Advantage Unlike current obturating materials, Vital-Dent is resorbable and promotes continued development of immature teeth, pulp revitalization and regenerative dentin, root strengthening, and long-term survival of the tooth. Vital-Dent eliminates difficulties of the only available revitalization procedure, revascularization therapy, with more consistent outcomes including root development, and a better fit with conventional clinic workflows including no phlebotomy and faster delivery.

Foundational Publications & Patents • Zaky et al. Effect of the periapical “inflammatory plug” on dental pulp regeneration: A histologic in vivo study. J Endod 2020 • PCT/US2019/023132 Regeneration of Vital Tooth Pulp

Juan Taboas, PhD University of Pittsburgh

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ITP Support Through the ITP program, biocompatibility and in vivo proofof-concept of Vital-Dent were demonstrated. In collaboration with the Regulatory Core, design control process has been implemented, and regulatory strategy established. With the Market Assessment and Commercialization Cores, user needs and the indication for market entry were defined and a commercialization strategy, including business and funding plans, was developed.

Key Inflection Points/ Regulatory Pathway • 510(k) anticipated • Submission of SBIR Phase II in Q3 2023 • Verification and validation of GMP product, GLP preclinical testing: estimated completion Q4 2025 • Regulatory approval and initiation of first-in-human study in Q3 2026

Opportunities for Partnerships • Seeking corporate partner to back fundraising efforts for first-in-human studies and facilitate market adoption • Academic partnership in studies that promote adoption and advance therapy development

Herb Ray, DMD University of Pittsburgh

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Dual Referral Model for Abaloparatide: Opening Opportunities for Osteoporosis Patients Desiring Dental Implants Over 70% of US adults are missing one or more teeth often due to periodontal disease, dental caries, or trauma. Tooth extraction leads to ridge resorption, characterized by a decline in alveolar bone quantity and quality, which may preclude dental implant placement without a secondary grafting procedure. However, current methods for bone grafting have limitations and not all treatments are predictable in patients with low bone density. One promising approach for augmenting bone and placing dental implants in osteoporotic patients is the use of bone anabolic drugs. Currently, there is no FDA-approved anabolic agent specifically indicated for dental patients. In the US, approximately 10 million people suffer from osteoporosis with another 44 million showing signs of osteopenia. These conditions are associated with tooth loss and significantly impact patients’ quality of life. Due to compromised bone quantity and quality, osteoporotic patients are also 18

more likely to have complications following implant placement or may not be eligible for implants at all. In the US it is estimated that as many as 50% of the 2 million patients who receive implants every year are post-menopausal women who suffer from this condition. Many more are not indicated for implants and unable to enjoy the benefits of fixed prosthetic teeth at all. Abaloparatide (ABL), a peptide therapeutic for osteoporosis treatment, is FDA-approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture or patients who have failed or are intolerant to other available osteoporosis therapy. ABL has demonstrated increased bone mineral density (BMD) and significantly reduced risk of new fractures. Importantly, in the treatment of osteoporosis, ABL tends to cause bone density gains, so the team is investigating WWW.MPWRM-DOCTRC.ORG

ABL as a candidate drug for dental implant placements in osteoporotic women. The project entered the ITP program in 2021, led by Dr. William Giannobile at Harvard University, with the goal of exploring the therapeutic potential of ABL to restore lost periodontium or enhance formation of implant-supporting alveolar bone. Support for the early research was provided by Radius Health, Inc., in the form of abaloparatide material. The ITP team is the first to investigate the use of this osteoanabolic drug class for dental applications. The current team includes accomplished junior researcher faculty and postdoctoral students with specialty training in oral surgery, implant dentistry, and periodontology. With support from the MPWRM Resource Center (RC), the team set out to establish the preclinical characterization of systemic ABL therapy to

treat alveolar bone loss and enhance dental implant performance. They are still in the process of refining and translating preclinical study data, which includes highly technical, surgical interventions designed to replicate clinical scenarios that occur in humans. Positive outcomes from these studies should position the team to submit an application for an investigator-initiated clinical trial on an approved drug where they hope to show that ABL can be used to reduce alveolar bone loss and enhance implant outcomes in osteoporotic dental patients. In collaboration with the RC’s Market Assessment Core and industry experts, the project team proactively sought to understand the potential clinical workflow using ABL drug in osteoporotic dental patients and how best to drive clinical adoption. Understanding that dentists who place dental implants are not the same clinicians who treat osteoporosis and prescribe ABL, the team

With the support of the ITP program, our research team has performed novel investigation of a potent anabolic drug in dental applications, which has culminated in important preclinical evidence generation that indicates a strong likelihood of technical and translational success. developed a creative “dual referral” model that describes the interactions between the physicians and the dentists who take care of these patients. In a true multidisciplinary WWW.MPWRM-DOCTRC.ORG

approach, leveraging the network of the RC, the team conducted in-depth interviews with 14 dental and bone health clinicians to test this “dual referral” model, gaining support for and evidence of how co-management between dental and medical providers could promote screening and early diagnosis, as well as optimize timing and reduce complications associated with dental implant placement in osteoporotic patients. The project team has made promising findings in its preclinical investigation of ABL for dental applications. This project has potential for rapid progression into the clinic, with a high likelihood of technical success. Key safety studies have already been conducted, and a significant understanding about this peptide’s mechanism of action and clinical value in medical indications has already been established. The project team is excited to see to the translational exit of ABL in clinical dentistry. 19

Abaloparatide to Treat Alveolar Bone Loss for Dental Implant Reconstruction Clinical Need Two million patients receive dental implants in the U.S. annually and up to 50% are post-menopausal women with osteoporosis. Osteoporosis patients may be denied implant therapy due to compromised bone quantity and quality. Predictable treatments to regenerate lost tissues around teeth or implants are limited, and no FDA-approved bone anabolic agents are available for this indication.

Solution A team of researchers led by Will Giannobile at the Harvard School of Dental Medicine is investigating the therapeutic potential of a systemic osteoanabolic drug, abaloparatide, to restore lost periodontium or enhance formation of implant-supporting alveolar bone. This approach offers easy dosing to regenerate lost periodontium and/or improve peri-implant bone density.

Competitive Advantage By taking advantage of easy delivery of abaloparatide, which is already clinicallyapproved for improvement of bone density in other indications such as osteoporosis, this approach may represent an improved access to drug therapies for periodontal and dental implant-related diseases that might otherwise not be as available due to limited reimbursement through typical dental insurance.

Foundational Publications & Patents • Miller et al. Bone mineral density response rates are greater in patients treated with abaloparatide compared with those treated with placebo or teriparatide: Results from the ACTIVE phase 3 trial. Bone 2019 • US10,568,937 Formulations of abaloparatide, transdermal patches thereof, and uses thereof

William Giannobile, DDS, DMedSc Harvard University 20

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ITP Support Upon entry into the ITP program in 2021, extensive preclinical characterization of the study drug had been performed for the osteoporosis indication. In 2022, initial demonstration of efficacy of the study drug for dental applications was achieved. Key safety studies have already been conducted and data generated from the ITP program may support auxiliary benefits of abaloparatide for alveolar bone in osteoporotic patients.

Key Inflection Points/ Regulatory Pathway • Abaloparatide has been FDA-approved since 2017 • Completion of preclinical data generation projected in Q2 2023 • First-in-human study anticipated to start at end of Q4 2023

Opportunities for Partnerships • Development with the MPWRM Commercialization/ Market Assessment Cores will explore commercialization and clinical adoption of technology

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Turning the Tide Together: A Pioneering Approach in Radiation-Induced Xerostomia Treatment Through Ultrasound-Assisted Non-Viral Gene Transfer Xerostomia, or dry mouth, is estimated to affect about 20% of the population. Due to extreme decreases in salivation, patients with xerostomia suffer from severe tooth decay, pain, loss of taste, decreased food mastication and increased oral infections, diminishing their quality of life. Specifically, xerostomia can be prevalent in head and neck cancer patients following radiotherapy where salivary glands receive collateral radiation damage. The advent of intensity-modulated radiotherapy (IMRT), wherein radiation beams are shaped to avoid vulnerable organs, such as the salivary gland, has been a great advance in reducing radiation-induced xerostomia, lowering the incidence from ~90% to ~40%. While amifostine could also be used as a radioprotectant to lower radiation-induced damage to salivary glands, it causes frequent and severe systemic side effects such as nausea and vomiting, which often leads to discontinuation of the treatment. Other treatments, such as saliva substitutes and saliva stimulants (e.g., pilocarpine and cevimeline) can provide temporary relief, but

their effectiveness is limited to patients that have significant amounts of functional saliva secreting cells remaining post-irradiation. This leaves a pressing unmet need for a new therapy.

Gene Transfer (UAGT) of AQP1, in development by the team of Drs. Isabelle Lombaert (University of Michigan) and Michael Passineau (Allegheny Health Network) aims to deliver a solution to this problem.

Aquaporin-1 (AQP1) gene therapy has been explored as an alternative treatment for these patients. An initial adenoviral delivery of AQP1 gene to the salivary gland has demonstrated successful outcomes to increase saliva production after irradiation in Phase I/II clinical trials; however, a highly inflammatory host response to this therapy was observed. Ultrasound-Assisted non-viral

UAGT is a technique that delivers a non-viral plasmid to cells through transient sonoporation and permeabilization of the cell membrane, thereby avoiding activation of the patient’s immune response.

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Gene therapy, while promising, has a complex set of regulatory requirements to ensure safety. As the only gene therapy program in the MPWRM Resource Center (RC) portfolio,

the RC Regulatory Core has been an integral part of this project since its matriculation in the program. The team has spent multiple sessions with the Regulatory Core to chart the preclinical translational development requirements to enable an FDA IND submission to gain approval to initiate the first-inhuman clinical trial. An initial GLP study to demonstrate the safety of UAGT without a vector was completed. In addition to the Regulatory Core, the Quality Assurance Core also supported this GLP study by completing an in-person pre-qualification visit of the GLP facility, preparing the study protocol in collaboration with the team, and reviewing and finalizing the study reports. With added pharmacology/toxicology regulatory expertise through the RC Core, the team has planned a streamlined regulatory approach to an IND filing in 2024. The Resource Center’s Market Assessment and Commercialization Cores have been an

The ITP program is the only currently available path wherein the wisdom and expertise of the various steps towards clinical translation are combined. integral part of this team to chart a road map towards the commercialization AQP1 UAGT. The team identified and interviewed a variety of clinical specialists, ranging from otolaryngologists to oncologists to oral maxillofacial surgeons, to understand the clinical management of radiation-induced

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xerostomia in head and neck cancer patients. Subsequently, the team investigated the medical reimbursement landscape to gain an understanding of potential reimbursement strategies. In addition, Dr. Lombaert has leveraged translational training resources at her home institution for the advancement of this project. Furthermore, with collective support from the home institution and RC experts, Dr. Lombaert has applied to and was successfully awarded the Frankel Innovation Initiative to support future GLP work. With the integrated support from the RC and the home institution, this project is poised to make great strides in the uncharted territory of gene therapy for radiationinduced xerostomia. With learnings from this indication, it is likely that the UAGT can be applied with other non-viral genes, serving as a platform technology that can be explored for various indications.

Non-Viral Aquaporin1 Gene Therapy to Restore Salivary Flow Clinical Need Radiotherapy is commonly used to treat head-and-neck cancers. Because of the anatomical proximity, salivary glands often receive secondary radiation damage, resulting in xerostomia. While intensity-modulated radiotherapy significantly reduces the incidence of radiation-induced xerostomia, a need still exists for patients suffering from xerostomia.

Solution Ultrasound-assisted gene transfer is based on sonoporation generated by ultrasound, enabling gene transfer into cells. The delivery of a water channel to glands in a large animal model restored salivary flow post-radiation to pre-treatment levels, demonstrating efficacy of our non-viral gene transfer approach.

Competitive Advantage While a recent clinical trial using a viral-based AQP1 gene delivery demonstrated an increase in saliva production, this approach has not advanced beyond Phase I/II trial due to side-effects generated by the adenovirus vector. With our non-viral based approach, it is anticipated that enhanced safety is provided in patients with AQP1 gene therapy throughout their lifetime.

Foundational Publications & Patents • Wang et al. Ultrasound-assisted nonviral gene transfer of AQP1 to the irradiated minipig parotid gland restores fluid secretion. Gene Ther 2015

Isabelle Lombaert, PhD University of Michigan

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ITP Support Since the start of the project in the ITP program in 2018, proof-of-concept for the anticipated product/ therapy has been established. The Resource Center Cores are supporting activities to enable the FDA IND submission. The ITP program has helped in deciphering the regulatory and commercialization path, and design/execution of studies needed for the FDA IND submission.

Key Inflection Points/ Regulatory Pathway • IND submission anticipated in 2024

Opportunities for Partnerships • Obtaining funds to initiate first-in-human trial

Michael Passineau, PhD Allegheny Health Network

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Oraxsys Therapeutics: From Academic Research to Commercialization, Harnessing Immunity for Periodontitis and Beyond Periodontitis is one of the most pressing oral health concerns today. In the US, almost half of adults over the age of 30 are thought to have periodontitis. Current clinical therapies for periodontitis focus on removal of bacterial species by scaling and root planing (SRP) or debridement, often in conjunction with local or systemic antibiotics. However, these treatments do not directly address the patient’s chronic in26

flammatory response, which has been found to be responsible for tissue destruction in periodontal disease. It has been recently shown that a subset of a patient’s own cells, called regulatory T cells (Tregs), may play a key role in periodontal disease; their WWW.MPWRM-DOCTRC.ORG

presence in gingival tissues seem to protect the patient from inflammation, whereas its deficiency causes progression of the disease. A project team lead by Drs. Steve Little (Professor and Chair of Chemical & Petroleum Engineering) and Charles Sfeir (Professor

and Chair of the Department of Periodontics and Preventive Dentistry) at the University of Pittsburgh (Pitt) is taking a reverse engineering approach to tackle periodontitis by recruiting Tregs to the patient’s gingiva. In particular, the team is leveraging the ability of C-C motif chemokine ligand 22 (CCL22) to recruit Tregs to the local site, with the goal of regulating the immunological response to reduce inflammation and slow the progression of periodontitis. The system is comprised of a resorbable microparticle-based delivery system to get the protein drug to the site with controlled release. The project had started at Pitt several years ago, with a key publication demonstrating the ability of the system to prevent bone loss mediated by inflammation in preclinical models of periodontal disease. The team had leveraged the translational training and commercialization programs at its home institution prior to joining the ITP program in 2018 to explore the regulatory and business aspects of the technology. With support from the MPWRM Resource Center, the project team continued the technical development of the CCL22releasing microparticles, including protocol development for protein production/ purification, manufacturing scale up of CCL22encapsulating particles, and evaluation of bioactivity/ stability of the released protein. Concurrently, leveraging the dental-specific expertise afforded by the Resource Center, the project team conducted interviews with clinical and industry experts with support from the Market Assessment and Commercialization Cores. Tapping into their network of periodontists and industry leaders with experience in bringing similar products to the market, the team understood firsthand the clinical workflow and practices, including the subset of patients for whom the clinicians are most likely to use this technology, potential timing of the treatment, what benefits it may provide, and considerations for future clinical trial design. From the business perspective, the project team uncovered some lessons learned from previous product launches and considerations for future business development opportunities including market positioning and potential industry and investment partners. In collaboration

with the Regulatory Core, the team analyzed the components of the product to consider manufacturing methods for CCL22 as well as the delivery system. As the formulation advanced, together with the Regulatory Core, the team conducted interviews with prospective GMP manufacturers.

Support from the ITP Program has been invaluable in helping Oraxsys answer key biological questions, develop assays critical for product characterization, facilitate early manufacturing process-development, and make important connections to experts in periodontal disease that have informed and improved out product development and company growth. In late 2021, the technology was optioned by Orange Grove Bio, a drug development and investment firm seasoned in successfully launching startups through university partnerships, forming Oraxsys Therapeutics. The partnership with Orange Grove Bio afforded the team access to additional expertise and resources, including a full drug development WWW.MPWRM-DOCTRC.ORG

team, further accelerating its progress. With much of the proof-of-concept work completed, under the leadership of its new CEO, Peter Alff, the project focused on the completion of the research phase and transitioning to the development phase towards FDA submission. Although development of a particle therapeutic containing bioactive immune-modulatory components poses some challenges with chemistry, manufacturing, and controls, the Oraxsys Therapeutics’ early scale-up attempts have proven successful, de-risking this aspect of the program significantly. The Resource Center introduced Oraxsys Therapeutics to several key opinion leaders and industry players in the periodontal space. Through conversations with these individuals, Oraxsys has grown to bring on specialized advice in periodontal disease treatment and product positioning, and has shared that “Guidance on commercial positioning and access to clinical expertise in the periodontal space have been and will continue to be the most important ITP value-adds for Oraxsys.” By leveraging the resources and expertise of Orange Grove Bio and the unique niche expertise of the Resource Center, the project continues to make strides towards an FDA submission. The team recently conducted an INTERACT meeting with the FDA, to confirm their strategy. With broad resident expertise from Orange Grove Bio and the Resource Center, the team is poised to submit an IND and initiate a first-in-human study in 2025 for the periodontal indication. Given the role of Tregs in inflammatory and autoimmune diseases and the effect of CCL22, it is anticipated that the CCL22releasing microspheres may be explored for other diseases whose etiology is driven by a similar mechanism. Leveraging this novel approach to harnessing the immune system to treat and control inflammation in the context of a disease, Oraxsys aims to develop a broad and highly-impactful therapeutic platform that not only disrupts the current paradigm in periodontal disease treatment, but will also be applied to numerous other inflammatory and autoimmune conditions.

Immunomodulatory Strategies to Treat Periodontal Disease Clinical Need Periodontitis is one of the most pressing oral health concerns today, affecting nearly half of adults over the age of 30 in the U.S. When left untreated, patients may require dental implants and bone grafting procedures. Antibiotics are currently used as an adjunct therapy to scaling and root planing, which remain the current gold standard of care for periodontitis. However, recent insights highlight the central role of chronic inflammation in the pathology of periodontal disease and it is this overactive immune response that is responsible for most of the damage and disease progression. Thus, new treatment modalities that target inflammation directly in the oral mucosa are greatly needed.

Solution A team at the University of Pittsburgh led by Dr. Steven Little and Dr. Charles Sfeir, DDS has identified a non-antibiotic, controlled release microparticle system that repairs the underlying immune-dysfunction responsible for tissue degeneration in periodontitis. This work has led to the founding of Oraxsys Therapeutics, a biotechnology company that is building on Dr. Little and Dr. Sfeir’s work to further develop a microparticle-based therapeutic that recruits regulatory T cells to the oral mucosa, controls chronic local inflammation, and induces immune-homeostasis, thereby reducing the destruction caused by periodontitis and promoting tissue regeneration.

Competitive Advantage Targeting the underlying chronic inflammatory pillar of periodontitis with an immune-modulatory, controlled release product (a novel treatment strategy that would synergize with SRP) is thought to overcome the current limitations in the treatment of periodontal diseases, peri-implantitis, and other oral inflammatory conditions.

Foundational Publications & Patents • Glowacki et al. Prevention of inflammation-mediated bone loss in murine and canine periodontal disease via recruitment of regulatory lymphocytes. Proc Natl Acad Sci USA 2013 • US8,846,098 Artificial Cell Constructs for Cellular Manipulation

Peter Alff, PhD Oraxsys Therapeutics/ Orange Grove Bio 28

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ITP Support The project entered the ITP program in 2018 with a robust data package describing the therapeutic mechanism of action and demonstrating preclinical efficacy in multiple disease models. Currently this work is being developed by Oraxsys Therapeutics, a company that has exclusive rights to the technology, and is driving all development efforts. Oraxsys plans to initiate a clinical trial for the treatment of periodontal disease. The ITP program has provided important assistance by enabling early process development and CMC efforts as well as insights into product positioning and market access strategy.

Key Inflection Points/ Regulatory Pathway • ORX-001 is a biological therapeutic; IND and clinical entry anticipated in 2024 and 2025, respectively • SBIR Fast Track application submission in Q3 2023 • CMC: Scaled-up production and characterization of API and microparticle at partner CDMO in Q4 2023

Opportunities for Partnerships • Seeking strategic partners in the dental medicine space to help facilitate product development and commercialization • Interested in speaking with Seed and Series A investors with an interest in and commitment to supporting companies developing therapeutics for treating inflammatory diseases and improving oral health

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nanoMAG and Emergence Dental: Improving the Shape and Predictability for Dental Bone Grafting In 2018, an ambitious project headed by nanoMAG, in partnership with investigators from the University of Pittsburgh (Pitt), entered the MPWRM Resource Center’s ITP program. nanoMAG is a medical device company developing and commercializing a bioabsorbable BioMg® alloy for craniomaxillofacial implant applications. They have been collaborating with Drs. Andrew Brown, a biomedical engineer (Clinical Assistant Professor, Department of Periodontics and Preventative Dentistry at Pitt) and Charles Sfeir, a dentist/scientist (Chair of the Department of Periodontics and Preventive Dentistry at Pitt) to develop a form stable, resorbable material for barrier membrane, mesh, and fixation systems. In the placement of dental implants, revision rates may reach ~25% due to insufficient bone quantity and/or quality necessary to adequately support an implant. The objective of this collaborative work was to take advantage of the mechanical strength afforded by the novel alloy to temporarily protect and expand the graft sites during healing. The project team is a true interdisciplinary alliance, bringing together expertise in mechanical/ materials science and engineering with clinical dentistry, working towards 30

the ultimate goal of improving outcomes for patients with insufficient bone. The original project concept started almost a decade earlier, around 2009. Prior to coming into the ITP program, the nanoMAG team had performed foundational work with the BioMg®. platform demonstrating safe and effective bone fracture healing. With support and backing from various sources including translational programs at Pitt and the NSF I-Corps program, the team conducted more than 120 customer discovery interviews to define the value propositions for the BioMg platform to expand into dental bone regeneration indications. Equipped with the early-stage prototype and an understanding of the unmet clinical and customer needs, the project’s early project goals in the ITP program were to establish manufacturing methods for the AmpliMag barrier membrane and select an apt protoWWW.MPWRM-DOCTRC.ORG

type that met the design criteria, as informed by clinicians. Upon in vitro optimizations, the prototype was tested in an in vivo model of vertical ridge augmentation, where challenges related to soft tissue closure were encountered. The Resource Center worked with the team to connect them with an internationally renowned expert who originally developed this pre-clinical model to understand its intricacies. This led to a thoughtful redesigning of the barrier membrane, resulting in a membrane better adapted to the ridge, improved alignment and screw retention, and the elimination of screw failure due to a more efficient implant driver. Poised with a significantly advanced version of the technology, a new company, Emergence Dental, was founded in 2019, based on the technologies from nanoMAG and the University of Pittsburgh, with Andrew Brown

as its CEO. Andrew is not only a biomedical engineer, but also has an advantageous combination of interests and experience with translational research and commercialization. Previously, Andrew was the Assistant Director of Commercial Translation Programs at sciVelo, an organization at University of Pittsburgh, whose purpose is to accelerate research of impact by converging scientific and business expertise to advance Pitt research to market-oriented solutions. With Andrew leading the team, Emergence Dental is developing regenerative products from metallic magnesium alloys, working in close association with nanoMAG. At this time, Emergence Dental is focusing on the continued development of the fixation system. This decision was driven by the system’s potential clinical value in eliminating fixation screw removal time and providing more rigid fixation compared to existing polymer-based fixation systems. Simultaneously, the approach enables the team to fast-track toward product commercialization due to regulatory and manufacturing considerations. Support and guidance from the

The dental-specific expertise provided by the Resource Center has been very valuable. Connections with industry partners and clinical key opinion leaders... would have been challenging to make alone. Market Assessment and Regulatory Cores of the Resource Center also contributed to this focused approach, and to the strategic commercialization plans for the company. In a round of in-depth discussions with various key opinion leaders facilitated by the Resource Center and its network, the team gathered that the application of AmpliMag may be broadened to 3-dimensional bone and ridge contouring. The team also learned that a magnesium mesh may be a stronger lead product from a clinical perspective than WWW.MPWRM-DOCTRC.ORG

a magnesium barrier membrane. By the end of 2020, Emergence Dental achieved significant milestones in securing investments from a seed stage investor and matriculation into a regional accelerator program. In conjunction with the connections with strategics and other industry experts through the Resource Center, Emergence Dental continues to further expand its network as they advance their fundraising efforts. More recently, Emergence Dental conducted two pre-submission meetings with the FDA, which helped them solidify their pre-clinical and clinical plans towards an FDA submission. With added clarity on these plans, the team anticipates the completion of GMP manufacturing runs, verification and validations, followed by GLP pre-clinical studies, and full clinical protocol development by the end of 2024. IDE submission and approval are projected in 2025, with de novo classification approval anticipated in late 2026. The team aims to partner with existing dental regeneration companies to undertake clinical trials and product marketing, shaping a revolutionary future in regenerative medicine. 31

AmpliMag Mesh and Mesh Fixation System Clinical Need Over 1M dental bone grafting procedures are performed annually in the US. In the most challenging procedures, revision rates may reach ~25%. Currently used regenerative devices are unable to offer form-stability, resorbability and gingival tissue friendliness. Thus, these procedures are highly technique-sensitive, prone to adverse events, and require invasive removal procedures.

Solution The AmpliMag Bone Grafting System provides the form-stability and gingival tissue friendliness needed to minimize adverse events and maximize bone regeneration. The system is fully absorbable which eliminates the need to retrieve hardware following healing. The AmpliMag system is based on a patented magnesium alloy developed by nanoMAG and device designs developed at the University of Pittsburgh.

Competitive Advantage No other barrier membranes or meshes offer both form-stability and resorbability which, taken together, enable maximization of alveolar ridge augmentation while obviating the need for device removal. Additionally, the magnesium alloy composition (BioMg250®) used in the AmpliMag devices contains only elements found in native bone, providing a safe environment for bone regeneration.

Foundational Publications & Patents • Brown et al. Porous magnesium/PLGA composite scaffolds for enhanced bone regeneration following tooth extraction. Acta Biomater 2015 • Decker et al. Development of BioMg 250 bioabsorbable implant alloy. In: Magnesium Technology 2018. TMS 2018 • US10,022,470 High Strength and Bio-Absorbable Alloy • US11,317,955 Magnesium Enhanced/Induced Bone Formation

Andrew Brown, PhD Emergence Dental, Inc.

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ITP Support Since entry into the ITP program in 2018, and the project has completed the design, manufacturing, and benchtop and pre-clinical testing activities for the AmpliMag barrier membrane, including a small pilot in vivo study, with financial and other support from the Resource Center. Additionally, the Resource Center has provided expert clinical, market, regulatory, and quality advice. In 2022, the AmpliMag Bone Grafting System reached a design freeze and begun GMP manufacturing following three FDA pre-submissions.

Key Inflection Points/ Regulatory Pathway • Closing bridge round and completing benchtop validation studies in 2023 • Closing seed round, completing GLP large animal study in 2024 • IDE clinical study anticipated to begin in 2025 • Completing clinical study and obtaining De Novo Classification as one product system (mesh and fixation system) in 2026

Opportunities for Partnerships • Emergence Dental is currently seeking dental regenerative partners to help inform clinical study and adoption strategies

Stephen LeBeau, PhD nanoMAG, LLC

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Ostiio’s Odyssey: Trailblazing a Transformation in Craniofacial Distraction Technology A collaboration between Dr. Jesse Taylor, Chief of Plastic Surgery at the Children’s Hospital of Philadelphia (CHOP) and Dr. Ari Wes, Plastic Surgery Resident at the Hospital of the University of Pennsylvania (Penn) began in 2012, when they set out to study multiple aspects of craniofacial disease, treatment paradigms, and surgical outcomes. Distraction osteogenesis (DO) in the craniomaxillofacial skeleton soon emerged. Although its benefits over traditional treatment modalities, such as reconstructive surgery, were evident, additional research underscored the limitations of DO in its current form. Currently available distractors have external components that protrude through the skin for manual engagement of the distractor - using a screwdriver - typically

twice a day for multiple weeks. As a result, Dr. Wes pursued a Master of Science in Translational Research, where his thesis, Novel Considerations in Craniomaxillofacial Distraction Osteogenesis, envisioned a fully subcutaneous, automated DO system for the CMF skeleton and formed the foundation of what would later become Ostiio. Ostiio, LLC was founded in 2017, when it was spun out of Penn to improve outcomes

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and experience for pediatric patients with craniofacial defects resulting from impaired growth of their skull or mandible. Through interviews with parent caregivers and surgeons, the team came to understand the critical challenges with DO – predisposition to morbidity such as soft-tissue infection due to the external component, unintentional patient/parent noncompliance, patient discomfort/increased analgesic use throughout

the distraction period, as well as the resulting scarring. The company was built around an idea to help the smallest of patients and their caretakers and doctors, to change the world of craniofacial distraction. With a fundamental prototype and unmet needs defined, the project was selected for funding by the ITP program in 2019. Learnings from the previous studies with the caregivers and surgeons helped the team define clinical performance criteria that would later form the basis of the most critical design inputs: the envisioned product would address the primary user objections to distraction - semi-buried implant, high caregiver burden, and limited surgeon control. However, at this earlier stage, it was not clear if the concept could be translated into a working prototype that would meet performance requirements and fit within the craniomaxillofacial anatomy. Miniaturization cannot come at the expense of meeting the distraction force performance specifications, so this design need has been a major challenge to overcome. Through the ITP program, the team built and tested its first proof-of-principle implant and handheld driver (HHD) prototypes, achieving the needed distraction force, validating the proof of principle. At the same time, the team raised additional funding through preseed round of financing to further support its product development. With the technical advancement of the prototype, the team held its first pre-submission meeting with the FDA, where they received guidance for their roadmap towards a 510(k) submission, which will likely not require a human clinical trial. In 2020, Ostiio brought on a CEO, Jessica DesNoyer, a seasoned professional with expertise in leading medical device development. With Jessica’s leadership and the support from the MPWRM Resource Center (RC), Ostiio formalized its product development process with a quality management system and transitioned the product development to a professional engineering firm. The team collaborated with the RC Regulatory Core to better understand the regulatory requirements for the 510(k), and a subsequent pre-submission meeting with the FDA helped

the team solidify their regulatory strategy to pursue multiple indications. To integrate customer input into their product design, the Ostiio team conducted a formative human factors study and an in-depth market assessment in collaboration with the RC’s Market Assessment Core, leveraging the RC network of clinicians. This study expanded their clinician and geographical

The ITP program has been an invaluable contributor to the success of our company. From the support provided by the Resource Center to the continued funding as we bridge the technology “valley of death”, the ITP program has been a true partner in facilitating Ostiio’s growth from early stage development into an investable MedTech company.

reach beyond the earlier studies that were conducted primarily at Children’s Hospital of Philadelphia (CHOP). Further, the findings re-emphasized the known challenges with DO, and helped the Ostiio team better refine their market fit and value. With this support from the RC, the Ostiio team is poised to integrate the learnings from multiple aspects of the project, including regulatory, market

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assessment, and technical development, to develop a device that not only meets user needs, but also streamlines their pathway towards a 510(k) submission. Under Jessica’s helm, the company has won multiple SBIR grants from both NSF and NIH to support different aspects of the fully-implantable distractor device. The team has also been named a MassChallenge 2021 Early Stage Program Gold Award Winner. From a cohort of 229 startups across all industries and technologies, this was formal recognition of the meaningful impact of Ostiio’s work on a national stage. Current plans with the ITP program will enable the team to complete a functional prototype system that achieves the performance specifications ready for preclinical testing. Upon verification of a system prototype that can complete a full distraction protocol in vivo without need for invasive manipulation, the team plans for a final prototype iteration (Gamma), which will be representative of the entire, final product and as close to the commercial product as possible. This prototype will incorporate any design changes resulting from findings of the animal study and a formative usability study and will be tested against performance requirements prior to design freeze. With these plans, Ostiio aims to submit at 510(k) in 2025, and strives to get this revolutionary device into the hands of patients, parent caregivers, and surgeons. By addressing the primary customer and patient concerns with DO, including the semi-buried form factor of distractors, Ostiio can also drive adoption of the technique for on-label adult indications, such as obstructive sleep apnea (OSA). The team is optimistic that within five years-time, the Ostiio distraction system will have significantly penetrated the pediatric market, accelerating adoption of DO over alternative treatment modalities and markedly improving quality of care for these patients. Further, as data mount supporting the safety and efficacy of mandibular lengthening as a treatment for adult OSA, their fully subcutaneous solution will make DO a viable choice for surgeons and patients where it is not a choice today.

Ostiio: A Smart, Fully-Implantable CMF Distractor Clinical Need Each year >200K newborns suffer from conditions that restrict growth of the skull or jawbone. Left untreated, these can have life threatening outcomes in an otherwise healthy child. However, treatments are complex and traumatic. Distraction is a gentler therapy that uses a device to slowly expand abnormal bone, but distractors are semi-buried, increasing complication risk; manual expansion is performed by parents, leading to noncompliance; and surgeons are blinded to treatment, forcing weekly X-rays and exams.

Solution Ostiio’s therapy uniquely solves pain points of distraction to improve patient outcomes and experience. The fully buried implant is expanded magnetically, removing the complication risk of semi-buried devices. The automated driver simplifies expansion, reducing parental noncompliance. The remote monitoring platform allows surgeons to track treatment progress, reducing post-op follow-up.

Competitive Advantage Distraction is the segment within the CMF device market that offers opportunity to differentiate, but technology advancement has been iterative with competitors focused on providing greater flexibility to the surgeon in the OR. Since treatment is home-based, Ostiio instead will transform how distraction is provided by parents and monitored by surgeons to improve patient outcomes and experience.

Foundational Publications & Patents • Kalmar et al. Forces exerted in craniofacial distraction osteogenesis. J Craniofac Surg 2022 • PCT/US2020/017918 Systems and Methods for a Smart, Implantable Cranio-maxillo-facial Distractor • PCT/US2023/060119 Systems and Processes for Distraction Control via Torque Sensing

Ari M Wes, MD Ostiio LLC

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ITP Support At entry to the ITP program, the project had early proofof-concept prototypes. The ITP program has enabled us to advance our integrated therapy from product conceptualization to late-stage, system-level prototypes. Working within an ISO 13485 certified quality management system, Ostiio has developed functional prototypes that exceed the most critical product specifications by >2x. In parallel, we have progressed key regulatory activities and completed important market validation work.

Key Inflection Points/ Regulatory Pathway • Pilot animal study in Q1 2024 • Design Freeze in Q3 2024 • Fundraising – A round of $1.5M closed by Q4 2023 • 510(k) to be filed Q1 2025

Opportunities for Partnerships • Investment opportunity: The company is currently seeking a Series Seed financing of $1.5M to complete our product design and validate its performance in animals

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A Future We Can All Smile About: Sequential Strategy for Dental Innovation Development at GreenMark Biomedical Dental caries, caused by the demineralization of enamel, is the most common chronic disease in the world. Globally, it is estimated that over $200 billion is spent annually on the management of dental caries and its complications, including both dental and medical expenditures. Caries is often treated surgically, beginning a cycle of increasingly invasive treatment that may eventually result in tooth loss or placement of an implant. However, there is a growing philosophy which focuses on preservation of enamel and teaches that early non-cavitated lesions, also called “white spot lesions”, can be repaired non-invasively by delivery of mineral ions and fluoride. Existing treatments include chairside fluoride varnishes, prescription high-fluoride toothpastes, over-the-counter lower fluoride toothpastes, and calcium phosphate-based remineralization agents. However, these available treatments do not 38

completely repair the lesion. Subsurface porosity leaves the area mechanically weakened with unaesthetic white spots. To address the need for regenerating hydroxyapatite crystals within the depth of subsurface carious lesions, GreenMark Biomedical, in collaboration with partners from the University of Michigan (U-M), are developing a targeted biodegradable starch nanoparticle capable of delivering minerals

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and fluoride specifically to carious enamel. The earlier technology was borne through the Ph.D. work of Dr. Nathan Jones, currently the V.P. of Technology at GreenMark. Several of the foundational patents were licensed from the U-M to GreenMark, which was founded in 2016. The company has spearheaded the development of several dental products based on these technologies, and maintains its laboratory at the U-M’s Innovation Partnerships Startup Incubator.

compositions for remineralization. Together with MPWRM Resource Center and its experts, the team has developed a creative step-wise regulatory strategy and product launch plan for the therapeutic products that synergize with its diagnostic product, LumiCare™ rinse. With support from the Resource Center Market Assessment Core, the team conducted a focus group with dentists and dental hygienists to better understand the current clinical workflow in the diagnosis and treatment of non-cavitated caries, and how best to fit GreenMark products into this workflow. The focus group also explored benefits of remineralization to clinicians and their patients, as well as other drivers for making purchasing decisions and specific scientific/clinical evidence clinicians would want to see before incorporating this product into their practice. During the ITP program, the team faced technical challenges related to product form-factor and packaging. They recognized early on that the product needed to be delivered in a dry form to prevent premature release of the mineral payload, a feature critical to its performance. A previous iteration included a gel-based formulation that could be dispersed quickly on-site for easy brush-on application. However, it was soon discovered that attaining dosing accuracy with a small individually packaged quantities of powder was difficult. This led them to innovate a novel product formulation, resulting in the development of the dissolvable dental strip. When GreenMark joined the ITP program in 2018, they had already been working with starch nanoparticles as part of a diagnostic product for the detection of early cavities. This product is now on the market as LumiCare™ rinse, and contains starch particles that penetrate through the porous surface and adhere to early-stage carious lesions for enhanced visualization. The ITP program is supporting the development of the therapeutic product based on the same foundational technology for the remineralization of caries. Earlier activities supported by the Resource Center included characterization and optimization of the starch nanoparticle

This new innovation and the learnings from the focus group was integrated into their product development process, and in 2023, GreenMark launched CrystLCare™ Biorestorative, Fluoride-Free, a product “designed to provide immediate and long-lasting dental sensitivity relief.” The launch of this product will facilitate the continued development of the remineralization product. Up next in their stepwise approach will be the submission of the Fluoride-Plus version for FDA review and approval. GreenMark Biomedical has also been successful in raising external funds, leveraging the support from the Resource Center. To date, the team has won several SBIRs from

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Access to world-class research facilities, state-of-the art instrumentation and dental equipment, recognized dentistry experts, and commercialization resources (through the Resource Center), have accelerated our product development in a way that traditional research grant funding cannot. NIH, pitch competitions, as well as the Cellerant Best of Class Technology Award. GreenMark has also been active in fundraising, securing various investments, including from the U-M’s venture investment program. With the learnings from the other products in its armamentarium and the step-wise regulatory strategy, GreenMark is poised to conduct a pre-submission with the FDA in the next year to review the requirements for the remineralization claims for the starch nanoparticles in 2024, with a de novo submission to follow. It is the hope of the GreenMark team that their technologies are tools that dentists can use to find caries in their early stage, treat them non-invasively, and monitor the benefits of those treatments, thereby preventing cavitation and the need for surgical restoration. This will advance the quality of dental care, increase accessibility to patients that are limited from dental care due to fear and cost, and improve oral health outcomes, which is a future we can all smile about. 39

Targeted Remineralization Treatment Using Mineral Loaded Starch Nanoparticles Clinical Need Dental caries is the most prevalent chronic disease worldwide. The unmet clinical need is noninvasive treatment through subsurface remineralization of enamel, as current fluoride toothpastes & varnishes incompletely repair caries lesions. Our professional-use products treat both dental hypersensitivity and early-stage caries, to reduce discomfort, preserve precious enamel and improve oral health.

Solution We produce tiny positively charged, mineral-loaded starch particles, to target and release inside negatively charged tooth subsurfaces. In-situ degradation forms hydroxyapatite crystals, occluding dentinal tubules and enamel porosities. Our products, CrystLCare™ Biorestorative, Fluoride-Free and Fluoride-Plus, are easy-to-use dissolvable dental strips, 14 single-use doses in a Fliptop Pack.

Competitive Advantage Current fluoride products merely seal the extreme upper surface layer of enamel lesions, but targeting the subsurface enables non-surgical treatment of early-stage caries as well as sensitivity relief. Localized concentration of minerals and fluoride facilitates tooth structure regeneration through formation of apatite crystals, yielding superior treatment compared to currently available products.

Foundational Publications & Patents • Jones et al. Nanoparticle-based targeting and detection of microcavities. Adv Healthc Mater 2017 • Amaechi et al. Evaluation of a Novel Caries Detecting Oral Rinse. BDJ Open 2023 • US10,987,434 Detection and Treatment of Caries and Microcavities with Nanoparticles

Steven Bloembergen, PhD GreenMark Biomedical Inc.

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ITP Support The project entered into the ITP program in 2018, and since then, the program has supported the subsurface treatment concept based on targeted illumination with companion caries detection product, as well as the validation of treatment performance and safety, and implementation of medical device requirements and operations. GreenMark Biomedical, a 2016 “NewCo”, proposed its subsurface treatment based on targeted illumination with the companion LumiCare™ caries detection product. With support from the program, GreenMark established proof-of-concept, developed two CrystLCare™ products, demonstrated occlusion of dentinal tubules and enamel porosities, validated safety, scaled manufacturing & packaging, implemented Quality systems and a Device Master Record.

Key Inflection Points/ Regulatory Pathway • Secure Series A and initiate clinical studies for CrystLCare™ Biorestorative Remin products in 2023 • Further scale up manufacturing of the CrystLCare™ products in 2023-2024 • Secure regulatory clearance for CrystLCare™ Biorestorative, Fluoride-Plus DH product in 2023-2024 • CrystLCare™ Biorestorative, Fluoride-Free product: Class I Medical Device FDA-registered • CrystLCare™ Biorestorative, F-Plus: 1) 510(k) Class II/Fluoride Monograph, 2) De Novo Class II

Opportunities for Partnerships • Seeking strategic partnership with global dental supply company and/or distributors • Raising $10+ million Series A equity investment round

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From Academic Collaboration to RegendoDent, Inc.: One (Dentin) Bridge at a Time Vital Pulp Therapy (VPT) is a true innovation in regenerative biomaterials for endodontic treatment. Today, the only form of regenerative endodontic therapy available is a technique called revascularization, where the patient’s own blood is used to create a clot in the dental canal with the hope that the biologic nature of the autogenous material will support pulp regeneration. This technique has not been widely adopted by endodontists, and even less so by general practitioners (GPs), because of its unpredictable clinical outcomes. Consequently, a regenerative biomaterial that could produce more predictable results would very likely be well-received by dentists and patients.

RegendoGEL, a first in class resorbable, is a regenerative hydrogel with bioactive ingredients that stimulate the tooth’s own healing process. Key benefits of RegendoGEL include that it is biocompatible, resorbable and non-inflammatory; it is able to regenerate dental pulp and dentin; and it is easily applied into the pulp chamber. RegendoGEL will enable RegendoDent Inc. to provide a novel platform for dental, oral, and craniofacial (DOC) regenerative technologies. Currently the dental regenerative area of the DOC arena includes periodontal tissue, bone and soft tissue regeneration, but not dental pulp regeneration. Similar to dentin WWW.MPWRM-DOCTRC.ORG

and enamel regeneration products, dental pulp regeneration via RegendoGEL would provide a new and exciting opportunity for anyone working to advance regeneration in DOC indications. From the start, RegendoDent Inc. has been a stellar example of a collaborative, interdisciplinary project in the MPWRM Resource Center’s ITP program. The project began with a research collaboration between Tufts University and Oregon Health and Sciences University (OHSU), where the two Principal Investigators (PIs) combined their complementary expertise in scientific research and clinical innovation.

PI Pamela C. Yelick, PhD is a Professor in the Department of Orthodontics at Tufts University School of Dental Medicine, with adjunct appointments in the Genetics, Molecular & Cellular Biology Program, Tufts Graduate School of Biomedical Sciences, TUSM and the Department of Biomedical Engineering, Tufts School of Engineering. She is an internationally recognized leader in dental tissue engineering and craniofacial development, with over 120 peer-reviewed basic research publications, more than two dozen reviews, and over 500 abstracts since the year 2000. She has received national and international acclaim for her research on dental tissue and whole tooth tissue engineering and has participated in over 300 Invited Speaker Lectureships. Co-PI Luiz Bertassoni DDS, PhD is an Associate Professor of Restorative Dentistry at OHSU, and also holds appointments at the OHSU Center for Regenerative Medicine and Department of Biomedical Engineering. Dr. Bertassoni leads a multidisciplinary research group working on various aspects of biomaterials and tissue engineering. His recent work on bioprinting vascularized tissue engineering constructs has received extensive attention in the popular media, including Fox News, The BBC, The Guardian, Fox Business, Wired.com, Tech Crunch, and others, and was selected as one of the top 100 science stories of 2014 (#64) by Discover Magazine. Dr. Bertassoni’s research includes: the use micro-scale technologies and bioprinting for tissue engineering; nanoscale structural and mechanical properties of mineralized tissues; and various aspects of the emerging field of ‘organs-on-a-chip’. Combining their research and interests in the regenerative DOC field, Yelick and Bertassoni have been able to effectively move the RegendoGEL technology through the product development pathway toward clinical acceptance and ultimately to patients who would benefit from a product for regenerative endodontic treatment. When accepted into the ITP program, they expanded their collaborative efforts to universities involved with the MPWRM Resource Center (RC), including the University of Michigan, University of Pittsburgh

and the Wyss Institute at Harvard University. The RC was able to help the ITP team with a market assessment to clarify the indication and clinical need, and the value proposition for RegendoGEL. Clinical advisors for the RC worked with the team to assess clinical challenges and opportunities in the endodontic space. The RC also helped the team establish a commercialization plan and go to market strategies that would encourage clin-

All of the steps being undertaken in this phase of the project would not have been supported by other forms of research funding. Our regular discussions with the Market Assessment Cores regarding adoption and pricing have been especially helpful, and have helped us shape a unique value proposition that we will test with prospective customers. ical adoption of the product. Based on that commercialization plan, the new company RegendoDent Inc. was established in 2022, and a CEO was hired. Several ITP teams would benefit from an effective dental reimbursement strategy. RegendoDent is well positioned to achieve this through a collaboration with Renaissance Health Service Corporation (RHSC), the sole member of several non-profit dental insurance companies. WWW.MPWRM-DOCTRC.ORG

The RC also helped the RegendoDent team prepare a presentation to RHSC that resulted in a $100,000 research grant for the RegendoGEL project. This funding suggests that RHSC supports the significant potential value RegendoGEL offers for all elements of the dental reimbursement system as a regenerative therapy to restore natural tooth structures. Patients, providers, payers, and plan purchasers should all see the benefits of a product such as RegendoGEL. The RegendoDent team anticipates a relatively fast 510(k) regulatory strategy that will not require a human clinical trial for FDA submission. For potential strategic partners, the fact that the product will be cleared for commercialization without the time and cost of a clinical trial is a significant advantage. The RC regulatory core has been instrumental in assisting the team with the necessary documentation to implement this strategy. With a secured commercial partner and FDA clearance, a clinical development plan will be initiated to support additional claims for the regenerative superiority of RegendoGEL over currently available products. At that point, the product will have been on the market long enough for that clinical development plan to be grounded in real world clinical needs and experiences. An interinstitutional agreement for licensing between OHSU and Tufts has been finalized, and an option to license the technology by RegendoDent is underway. The RC Market Assessment and Commercialization Cores are working with RegendoDent to develop a market map and a target list of potential strategic partners. Through the RC industry network, RegendoDent Inc. has been able to interact with several companies and has multiple NDAs in place that will allow for exploration of commercialization partnership opportunities for RegendoGEL. The current RegendoDent goal for FDA submission and clearance by 2025 seems very achievable and will lead to this exciting technology being available to benefit patients in the very near future.

RegendoGEL: A Bioinspired Hydrogel System for Endodontic Therapy Clinical Need Dental caries is the most common non-transmissible infectious disease in the world. If untreated, caries lesions will progress to the dental pulp, exposing it to infection. Standard of care techniques involve removing infected pulp and capping the defect with inert material, or root canal therapy. Currently, there are no clinically available materials that regenerate the pulp-dentin complex.

Solution A team led by Luiz Bertassoni, DDS, PhD and Pamela Yelick, PhD has developed a novel material, RegendoGEL, intended to be the first-of-its-kind clinical product to promote vital pulp and dentin regeneration. RegendoGEL contains key bioactive molecules present in healthy teeth that naturally promote dental pulp and dentin regeneration and may be used for pulpotomies.

Competitive Advantage Compared to non-degradable silicate/calcium hydroxide-based products currently used for endodontic treatments, RegendoGEL is a soft, biodegradable hydrogel material. RegendoGEL stimulates cells to migrate into the defect site and regenerate living dental pulp tissue and dentin in 5 days. RegendoGEL is designed as a readyto-use product that can easily be applied using routine dental procedures.

Foundational Publications & Patents • Cunha et al. 3D-printed microgels supplemented with dentin matrix molecules as a novel biomaterial for direct pulp capping. Clin Oral Investig 2023 • PCT/US2018/035200 Dental pulp constructs • US11,278,474 Pulp regeneration compositions and methods of forming and using the same

Luiz Bertassoni, DDS, PhD Oregon Health and Science University 44

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ITP Support The project entered the ITP program in 2018, and since then has leveraged support from the Resource Center Cores including Regulatory, Preclinical Studies, microCT, Histology, Statistics, Market Assessment, and Commercialization. The ITP program has supported two in vivo experiments that have provided key results that catalyzed the formation of a new company, RegendoDent, Inc. Further, the program provided networking opportunities that led to third-party funding enabling the hire of a CEO for the company and preparing the company to attract potential business partners.

Key Inflection Points/ Regulatory Pathway • Submit STTR grant & seed raising in Q3 2023 • Complete GLP Validation in Q4 2024 • 510(k) submission in Q1 2025 • First in human study anticipated to start upon FDA clearance

Opportunities for Partnerships • Series A Funding for RegendoDent, Inc. to launch RegendoGEL and conduct a clinical trial

Pamela Yelick, PhD Tufts University

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RevBio’s Tetranite : Redefining Bone Repair and Regeneration Through Groundbreaking Bioadhesive Innovation ®

RevBio is a science and engineering start-up focused on solving the unmet clinical need for a biomimetic bone adhesive that can be used to augment bone ridges. The solution, Tetranite®, is a cohesive, injectable, and self-setting material that can be applied in wet surgical environments. It does not get washed away during the application process, then hardens within minutes to create adhesive bonds to surrounding bone in the shape of a bone ridge as it cures. As part of the MPWRM Resource Center (RC), RevBio is exploring these robust characteristics of Tetranite to enhance oral bone regeneration in challenging situations where conventional particulate or block grafts have been ineffective or unpredictable, at best.

products – especially in non-space making defects – due to their challenging handling properties. As most products lack structural integrity, they typically require the use of fixation or containment devices to stabilize the graft and membranes to prevent ingrowth of fibrous tissue that impedes bone regeneration and remodeling. The application of Tetranite with its distinctive adhesive properties is expected to obviate the need for these devices, making the procedure less technique sensitive with more predictable outcomes.

The development of Tetranite was already in progress for other indications when the project entered the ITP program in 2018 with a focus on its development for dental bone grafting applications. Through market research of their own, the RevBio team learned that 70% of all patients who receive dental implants require some form of bone grafting prior to implant placement, yet most dentists remain dissatisfied with existing bone graft

With the RC’s Market Assessment Core, the team conducted rounds of interviews with clinical and industry experts in the dental bone grafting space. From these discussions, the RevBio team gained a deeper understanding of the challenges in dental bone grafting and the associated market dynamics, including the limitations of competitive products and their pricing. With the learnings, the team continued to hone their target

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indication, where the unique properties of Tetranite can best be leveraged and its value optimized. The Market Assessment Core also provided the team with market data related to specific indications as well as bone graft types and projected growth opportunities in the market. Initial studies conducted in the ITP program allowed the formulation to be fine-tuned, material characterized, and proof-of-concept efficacy studies to be completed. With this formulation, the project proceeded with a GLP preclinical study using a model discussed with the FDA in a pre-submission meeting. Due to the unique preclinical model, the GLP facility and vendor was selected in collaboration with the RC’s Regulatory and Quality Assurance Cores and the selected facility was pre-qualified by the Quality Assurance leads of RevBio and the RC’s Quality Assurance Core. As this study got underway, issues with the preclinical model emerged. Upon an in-depth review of the complica-

tions with the RC’s Regulatory and Market Assessment Cores and clinical experts, the study model was thoughtfully re-designed. With support from the RC, the team successfully obtained concurrence from the FDA that the revised model would be appropriate for the GLP preclinical study. The RevBio team also conducted material characterization and biocompatibility testing, and developed a unique sterile packaging for the product. To refine the prototype, the RC helped organize several user validation and human factor engineering tests, including in-person user handling trials. In collaboration with the RC Market Assessment Core, the team developed plans and recruited >10 clinicians to participate in its in-person user handling trials, leveraging co-timing with professional meetings where many of these key opinion leaders (KOL) clinicians were in attendance. The practitioners were brought together, and provided with the RevBio prototype in its packaging, where they had first-hand experience using it in a simulated clinical environment. The team received valuable feedback from the clinician

Overall, the Resource Center and its internal resources have played an important role in advancing the development of this high-potential product. participants, which resulted in changes to the kit design and reduction of the packaging footprint, as well as many good ideas regarding education and training that will drive broader clinical adoption. RevBio continues to push boundaries and explore multiple indications for Tetranite. The product is in clinical stages for implant stabilization, cranial flap fixation, and veterinary use. For its bone indications, the team also conducted an in vivo experiment to study Tetranite’s ability to regenerate bone in microgravity conditions -- on the WWW.MPWRM-DOCTRC.ORG

International Space Station (ISS). In fact, this is Tetranite’s second trip to space, following a previous in vitro experiment. Sponsored by the ISS National Laboratory, Tetranite was launched on SpaceX’s 26th Commercial Resupply Services (SpaceX CRS-26) mission, where the microgravity in space is used to simulate conditions where bone growth and regeneration is compromised. In addition to the support from the MPWRM Resource Center and the National Institute of Dental and Craniofacial Research, RevBio has garnered significant federal grant funding from several other institutes of NIH, including National Institute on Aging and the National Institute of Neurological Disorders and Stroke. They have also been successful during several rounds of fundraising. The team is results-driven and has taken full advantage of the RC expertise in designing pre-clinical studies, handling sessions, regulatory strategies, and quality oversight, moving quickly towards their first-in-human studies. For the dental bone grafting indication, the team is striving towards an IDE submission in late 2024. 47

Optimization of a Novel Organic-Mineral Bone Adhesive for Dental Bone Grafting Clinical Need Based on market research conducted by RevBio, almost half the patients that seek a dental implant supported crown suffer from chronic edentulism and require extensive bone grafting to rebuild their alveolar ridge. Over 30% of the time, these grafting procedures achieve suboptimal results and require some form of re-grafting adding to the overall cost, treatment time, and morbidity for these patients.

Solution RevBio has developed Tetranite® Adhesive Dental Bone Scaffold (TN-ADBS), a synthetic, porous, cohesive organic-mineral bone scaffold with adhesive properties that resorbs and is replaced by bone on a timescale commensurate with existing graft materials but does not require ancillary fixation or containment devices.

Competitive Advantage Currently available particulate bone grafting products require significant surgical skill to apply. In contrast, TN-ADBS is both cohesive and adhesive which makes it easy to use. The product will reduce the overall time necessary to perform ridge augmentation procedures, better maintain graft volume over time, and minimize the need for re-grafting.

Foundational Publications & Patents • Kesseli et al. Identification of a calcium phosphoserine coordination network in an adhesive organo-apatitic bone cement system. Acta Biomater 2020 • Kirillova et al. Bioinspired mineral–organic bioresorbable bone adhesive. Adv Healthc Mater 2018 • US8,232,327 Tetra Calcium Phosphate Based Organophosphorus Compositions and Methods • US8,765,189 Organophosphorous & Multivalent Metal Compound Compositions and Methods

Joseph Fiorellini, DMD, DMedSc Penn Dental Medicine 48

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ITP Support The project entered the ITP program in 2018, enabling RevBio to initiate the dental bone grafting project. Through the program, RevBio accomplished key marketing milestones, including market surveys to validate the clinical need and the lack of any known competitive products with a comparable clinical value proposition. The Quality Assurance Core aided in performing a supplier quality audit for animal study, and the program helped recruit influential surgeons for validation studies. The Resource Center and its internal resources have been critical in advancing the development of this high-potential product.

Key Inflection Points/ Regulatory Pathway • Fundraising – Close convertible note round ahead of anticipated Series A round by end of Q2 2023 • Device-led combination product; IDE submission scheduled for Q3 of 2024

Opportunities for Partnerships • Distribution of the product: Strong industry distribution partner that can represent the product globally • Investment opportunity: Currently seeking Series A financing of $25M to initiate multiple clinical studies

George Kay, DMD RevBio

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Connecting the Dots and Building Partnerships A Program With National Reach Ambitious ventures of the MPWRM Resource Center aim to transform patient lives by accelerating the translation of groundbreaking basic research to real-world clinical applications. The infrastructure of the Resource Center and the ITP program is not only a model for the dental, oral, and craniofacial (DOC) space but can be translatable and scaled in other clinical therapeutic domains. Training and education is also a main component of the Resource Center, with more than 100 researchers and investigators having gone through the ITP program.

Leaving a Lasting Mark Our efforts have a resounding impact across academia, industry, and the broader public. The regenerative technologies we support span diverse facets of DOC healthcare, ranging from craniofacial bone regeneration to specialized dentistry fields like periodontics and endodontics. Many of the individuals who participated in the ITP program are clinicians, scientists, and engineers, now equipped with the interdisciplinary skills and mindset for translational research and commercialization. Consequently, we are fostering a shift in culture, from basic and translational research to product development and clinical adoption, moving forward towards tangible, market-ready solutions for patients. Moreover, our activities contribute to economic development, spawning over four new companies to date, generating more than 150 jobs. The MPWRM Resource Center is dedicated to making connections and nurturing partnerships that enhance public health.

Supporting DOC Regenerative Initiatives We invite you to join us in our mission to advance DOC public health through groundbreaking innovations and support their translation into the market and clinical adoption. From operations to training and education to translational and clinical research to commercialization and clinical adoption, we are actively seeking creative partnerships to sustain our activities, each deeply rooted in our commitment to bringing promising therapeutic solutions to patients across the globe.

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Nothing happens without a great idea - we try and focus on what the specific project needs... anything we can do along that... transition pathway is what we’re focusing on to get it to the patient.

My laboratory has been developing a... medical device... for about 15 years, and now we’re at a point where we can translate this device into humans. The Resource Center has proven to be a valuable resource for us to get through that last hurdle.

The Resource Center provides an invaluable support structure with a focus on key business aspects.

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Operating Committee Jeanne Ambruster The Avenues

William Giannobile Harvard University

David Kohn University of Michigan

Vicki Rosen Harvard University

Connie Chang ONL Therapeutics

Ken Hargreaves University of Texas Health Center San Antonio

Paul Kostenuik Phylon Pharma Services

Charles Sfeir University of Pittsburgh

David Mooney Wyss Institute at Harvard University

Tony Torres University of Pittsburgh

Kay Fuller Medical Device Regulatory Solutions LLC

Darnell Kaigler University of Michigan

Contacts Interdisciplinary Translational Project (ITP) Program Mutsumi Yoshida University of Michigan – School of Dentistry 1011 North University Avenue, Room 3303 Ann Arbor, Michigan 48109 (734) 764-4622 | yoshidam@umich.edu

Katie Moynihan Blue Ridge Bio

William Wagner University of Pittsburgh

Program Administration Patrick Cantini University of Pittsburgh/ McGowan Institute 450 Technology Drive, Suite 300 Pittsburgh, Pennsylvania 15219 (412) 624-5209 | cantinip@upmc.edu

Michigan-Pittsburgh-Wyss Regenerative Medicine Resource Center is supported in part by the National Institute of Dental & Cranfiofacial Research of the National Institutes of Health under Award Number U24DE029462. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.