# Evaluation of Anti-Inflammatory Delivery from Mechanically-Activated Microspheres in the Context of Cruciate Ligament Injury

> **NIH VA I21** · PHILADELPHIA VA MEDICAL CENTER · 2024 · —

## Abstract

From mouse to man, traumatic injuries to the joint cause inflammation and, when the instigating injury remains
uncorrected, persistent inflammation culminates in irreversible degradation of all joint structures. In companion
animals, such as dogs, cranial cruciate ligament (CCL) disease is one of the most common causes of lameness
and is the leading cause of degenerative changes in the stifle joint. A number of therapies have been developed
to treat inflammation associated with persistent joint pain, including direct joint injections of non-steroidal anti-
inflammatories and intra-articular (IA) glucocorticoid and systemically delivered biologic therapies, among others.
However, most IA therapeutics are rapidly cleared from the joint via the synovium within 24-48 hours. To sustain
drug delivery in the mechanically loaded joint, our team recently developed a novel delivery system based on
PLGA microparticles that are designed to rupture under specific mechanical loading parameters (MAMCs). Our
data show that biologic therapies (including receptor antagonists such as IL-1Ra) can be encapsulated at high
efficiency and release active factors through both mechanically induced rupture and/or passive degradation of
the MAMCs. When injected into a minipig synovial joint, empty MAMCs are well tolerated, and progressively
release their contents over a two-week period. While promising, this technology has not yet been extensively
evaluated in a naturally occurring spontaneous injury model. In this proposal, we will first (Aim 1) develop
MAMCs delivering the clinical formulation of IL-1Ra (AnakinraTM) and test their efficacy in attenuating
inflammatory signaling in canine synovial tissue organ culture. Next, we will assess this technology in client
owned canines subsequent to presentation of CCL injury and compare the safety and efficacy of IA IL-1Ra
MAMCs to both systemic and IA delivery of unencapsulated soluble IL-1Ra . In these dogs, as well as humans
with ACL injuries, several weeks generally pass between the timing of knee injury and the surgical repair, during
which time inflammatory factors are present in the joint. Aim 2 will test the hypothesis that sustained release of
anti-inflammatory therapeutics after injury, but before surgical repair, will better limit joint inflammation and
improve patient recovery after surgical repair when compared to systemic or IA delivery of unencapsulated
soluble IL-1Ra. Successful completion of this study will advance a new technology towards human clinical
implementation and validate, for the first time, the safety and therapeutic efficacy of MAMC-delivered IL-1Ra in
a pilot clinical trial (executed through the PennVet Veterinary Clinical Investigation Center) in client owned
canines. These pilot data will set the stage for subsequent larger and longer lasting clinical trials, as well as
application of this novel drug delivery platform to other injury scenarios in which quelling inflammation improves
long term outco...

## Key facts

- **NIH application ID:** 10798447
- **Project number:** 1I21RX004628-01A1
- **Recipient organization:** PHILADELPHIA VA MEDICAL CENTER
- **Principal Investigator:** Robert L Mauck
- **Activity code:** I21 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10798447

## Citation

> US National Institutes of Health, RePORTER application 10798447, Evaluation of Anti-Inflammatory Delivery from Mechanically-Activated Microspheres in the Context of Cruciate Ligament Injury (1I21RX004628-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10798447. Licensed CC0.

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