UC San Diego

Traumatic brain injury (TBI) is a critical public health concern affecting millions of people globally per year. The primary trauma initiates a complex cascade of secondary injury which can extend for days to weeks post-injury and involves disease hallmarks like ectopic protease activity, vascular dysregulation, and neuroinflammation. Unfortunately, several hurdles constrain clinical translation of TBI therapeutics, including limited passive accumulation into injured brain tissue. As an alternative approach, my thesis leverages the extracellular matrix (ECM) to target the brain after TBI. Native brain ECM is an attractive candidate for active material targeting via affinity ligands or click chemistry to improve selectivity and distribution within the injured brain. Additionally, decellularized ECM derived biomaterials have previously demonstrated injury-specific deposition, retention, and therapeutic repair in preclinical models of disease, and are thus promising candidates for investigation within TBI.

First, the native brain ECM was leveraged as a scaffold to improve delivery and function of a nanosensor for TBI. We performed an in vivo screen of peptide sequences that bind ECM constituents in the injured brain and found that hyaluronic acid (HA) targeting peptides increased nanomaterial distribution within the injury. We then utilized HA targeting to improve delivery and function of a protease-responsive imaging material. The addition of HA targeting peptides to our fluorogenic activity-based nanosensor for TBI improved nanosensor activation and enabled robust 3D visualization of protease activity within a cleared brain. Second, we developed a novel in vivo chemical targeting approach for TBI by leveraging the extracellular fibrin clot as a scaffold for in situ click chemistry. We delivered strained cyclooctyne (SCO) modified fibrinogen which incorporated within the injured brain. The SCO-modified clot was subsequently utilized for intra-injury capture and retention of diverse materials including a small molecule azide-dye, 40kDa azide-PEG, and PEG-catalase antioxidant. Third, we investigated the pharmacokinetics, biodistribution, and therapeutic potential of an infusible extracellular matrix derived biomaterial (iECM) within TBI. iECM accumulated and was retained within the injured brain and a multi-dose regimen was established to optimize delivery. Further, iECM reduced vascular permeability at the injury and modulated pro-inflammatory and neuroprotective genes. Taken together, we demonstrate the utility of ECM as a scaffold for material targeting, and as an injury-homing biomaterial therapeutic, within TBI.