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Small molecule drugs accelerate implantosseointegrationNpas2 modulating compounds to enhanceimplant osseointegrationDr. Ichiro Nishimura, D.D.S, D.M.Sc, D.M.D. &Dr. Akishige Hokugo, D.D.S., Ph.D.UCLA School of DentistryLos Angeles, CA

OverviewTitanium (Ti)-based biomaterials have been widely adopted in implantablemedical devices for orthopedic and dental applications, yet the mechanismsof osseointegration remain unknown.UCLA researchers have identified that the molecular circadian clock geneneuronal PAS domain protein 2 (Npas2) plays an important role in theestablishment of osseointegration induced by Ti biomaterials with a complexsurface modification.These scientists have identified several Npas2 upregulating small moleculecompounds that hold promise for accelerating and/or re-establishing implantosseointegration.2

Biomaterials interface with living tissue for atherapeutic, medical purpose.Biomaterial implants improve the outcomesof patients suffering from chronic conditionsor traumatic injury.These materials must be compatible withthe body in order to allow for properosseointegration– the direct, functionalconnection of a biomaterial with bone.Researchers are seeking methods toincrease osseointegration, and therefore theeffectiveness, of biomaterial implants.CREDIT: FRONTIERS3

Titanium alloy biomaterials have been applied to awide range of implantable medical devices.Ti-based biomaterials induce the leastforeign body reaction, minimal fibrosis, andallow osseointegration without a layer ofsoft tissue encapsulation.Surface functionalized Ti implants havebeen shown to improve and accelerate theosseointegration process.CREDIT: AZO MATERIALSThe underlying mechanisms of surface functionalized Tiimplant osseointegration are not fully understood.4

Identifying the osseointegrationmechanism.UCLA RESEARCHERS HAVE ELUCIDATED THE MOLECULAR MECHANISM OFOSSEOINTEGRATION, AND IDENTIFIED NPAS2 MODULATING COMPOUNDSTHAT CAN BE USED TO ENHANCE IMPLANT OSSEOINTEGRATION.

Team: Industry leaders in dental and orthopedicimplants.Dr. Ichiro Nishimura, D.D.S, D.M.Sc,D.M.D.UCLA School of DentistryDr. Akishige Hokugo, D.D.S., Ph.D.Plastic and Reconstructive Surgery, UCLASchool of DentistryFounder, Jane and Jerry Weintraub Center forReconstructive Biotechnology6

Neuronal PAS domain protein 2 (Npas2) is requiredfor osseointegration.The molecular circadian clock gene Neuronal PAS domain protein 2 (Npas2) was found to be highlyassociated with the successful development of osseointegration.Impaired osseointegration in Npas2 /- andNpas2-/- mice, demonstrated by decreasedcollagen fibers compared to WT.Npas2 facilitates enhanced osseointegrationthrough alternative neuroskeletal regulatorypathways induced by Ti biomaterials with acomplex surface modification.7MORINAGA ET AL, BIOMATERIALS (2019)

Several compounds that upregulate Npas2expression were identified to enhanceosseointegration.8MORINAGA ET AL, BIOMATERIALS (2019)

Market Opportunity

The generalized market for dental implants ispredicted to reach 5 billion in 2023.Dental disease in the most prevalent chronic disease on a global scale.Analysis of the dental implant global market was performed with information from BCC Report HLC218A.10

Any company utilizing Ti-based biomaterials for implants may takeadvantage of Npas2 enhancers for increased osseointegration,without the need for complex surface modification.Analysis of the dental implant global market was performed with information from BCC Report HLC218A.11

Invention competitionHigh osseointegrationThis technologyCaPBPs on3MStraumannSwissplus (Zimmer)ProActive (Neoss)Implant adjunctsT3 (Zimmer)Poor osseointegrationImplants12

The market for dental and osteopathic implants is in agrowth stage, and favorable for manufacturers entry.Increasing oral diseases leading to toothloss, a rising geriatric population, largerhealth care spending and disposableincome, and the rapid development andadvancement of dental technology are keymarket drivers.There is a clear unmet need for enhancedosseointegration of implants.Npas2 modulating compounds may be usednot only for dental implants, but areapplicable to other implantable biomaterials.CREDIT: IMAGECARE DENTAL13

Thank YouUCLA TECHNOLOGY DEVELOPMENT GROUP10889 WILSHIRE BLVD., SUITE 920LOS ANGELES, CA 90095310.794.0558 l info@tdg.ucla.eduwww.tdg.ucla.eduCONNECT WITH US @UCLATDG

Table: Validated compounds modulating Npas2expression15MORINAGA ET AL, BIOMATERIALS (2018)

Table: Validated compounds modulating Npas2expression16MORINAGA ET AL, BIOMATERIALS (2018)

UCLA School of Dentistry Founder, Jane and Jerry Weintraub Center for Reconstructive Biotechnology Team: Industry leaders in dental and orthopedic implants. Dr. AkishigeHokugo, D.D.S., Ph.D. Plastic and Reconstr