# A new model of regenerative healing via inflammation-modulating biomaterials

> **NIH NIH R01** · LANKENAU INSTITUTE FOR MEDICAL RESEARCH · 2020 · $705,109

## Abstract

Abstract
 The ability to regenerate tissue in mammals has remained elusive. While the use of stem cell populations
in the context of bio-scaffolds has shown promise as a potential means of replacing lost, damaged, or
diseased tissue, significant challenges remain. An alternative approach is to attempt to evoke a classical in
situ regenerative response emulating that seen in lower species such as newts. While this trait was thought
to be lost in evolution, our observation (Heber-Katz) that the MRL mouse and related strains have a
significant spontaneous regenerative capability demonstrates that the trait is retained in mammals. Studies
over the past almost 20 years have culminated in the identification of the HIF-1α (hypoxia inducible factor)
pathway as the central actor regulating regeneration in mice. HIF-1α is significantly elevated during the early
phases of wound healing in MRL mice and inhibiting HIF-1α with si-RNA blocks regeneration entirely. When
we mimicked this HIF-1α response in otherwise non-regenerating Swiss Webster mice the regeneration trait
was conferred with the faithful replacement of tissue architecture indistinguishable from normal tissue. This
was achieved using the PHD inhibitor 1,4-DPCA in a novel biomaterial construct (Messersmith) leading to
the stabilization of high levels of HIF-1α in vivo. In this current proposal, we provide preliminary results
suggesting that impressive healing is also seen in a mouse model of periodontal disease, ligature-induced
bacterial accumulation leading to an inflammatory host response with bone loss (Hajishengallis model). We
show that bone recovers, the periodontal ligament (PDL) is restored, and an unusually robust stem cell
response in the tooth pulp and in periodontal tissue is found. We will use advanced molecular design to
produce a biomaterial capable of achieving single dose and local delivery vs. the current three-dose delivery
system. In addition to yielding a novel soft and bone tissue regeneration therapy, we believe that this system
provides an impressive landscape of phenomena that will yield important mechanistic information about in-
situ regenerative responses in oral tissues.
 In Aim 1, we will create new biomaterials to yield extended drug release to provide a single-dose treatment
with rapidly degradable gels; in Aim 2, we will examine the effect of drug preparations, both original and new,
on bone and PDL loss and regrowth using microCT and molecular analysis; in Aim 3, we will further explore
the metabolic response after modulating HIF levels; and in Aim 4, we will determine mechanistic factors
involved in the inflammatory, overall immune, and stem cell responses.
 In conclusion, a successful in-situ drug-induced regenerative therapy would significantly advance the
treatment of periodontal disease beyond current surgical procedures.

## Key facts

- **NIH application ID:** 9982904
- **Project number:** 5R01DE021104-10
- **Recipient organization:** LANKENAU INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Georgios Hajishengallis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $705,109
- **Award type:** 5
- **Project period:** 2011-05-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982904

## Citation

> US National Institutes of Health, RePORTER application 9982904, A new model of regenerative healing via inflammation-modulating biomaterials (5R01DE021104-10). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9982904. Licensed CC0.

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