Wielding the Double‐Edged Sword of Inflammation: Building Biomaterial‐Based Strategies for Immunomodulation in Ischemic Stroke Treatment

Abstract

Stroke is a leading cause of disability with no current treatment to regenerate lost brain tissue. Innovative preclinical and clinical trials have attempted to improve stroke recovery by promoting cell survival, downregulating astrogliosis and inflammation, and improving neurogenesis and angiogenesis; however, the complexity of stroke pathophysiology raises many challenges. Previous attempts to grossly inhibit the inflammatory reaction failed to improve stroke outcomes, prompting scientists to explore selective modulation rather than unbiased inhibition. Although experimental studies involving immunomodulation are successful, strategies have largely failed in the clinic. Some of these approaches are hindered by poor delivery efficiency or cell survival, challenges that could be at least partially overcome using biomaterials. Biomaterials may enhance immunomodulatory processes by improving drug and cell delivery to the injured tissue. Furthermore, the materials themselves can support healing and may be designed to act as immunomodulators, thereby contributing to tissue regeneration and endogenous repair processes. Described here are novel biomaterial-based strategies to modulate the immune response after ischemic stroke, with an emphasis on extracellular matrix mimetics and hydrogels for local delivery of drugs and cells. Finally, a future perspective is described, highlighting the potential of these therapies to achieve clinical translation and improve patients' functional repair.

Towards clinical translation of ‘second-generation’ regenerative stroke therapies: hydrogels as game changers?

“…For preclinical chronic stroke applications, hyaluronan is typically blended with methylcellulose, another naturally occurring polymer, to impart thermoresponsive properties that enable in situ forming following injection into the brain [9]. Hyaluronan-methylcellulose (HAMC) hydrogels have been primarily pioneered by the Shoichet laboratory specifically for applications in chronic stroke and meet all of the technical considerations with regard to biocompatibility, material optimisation and stroke-and payload-dependent suitability.…”

“…This could have profound implications for material-based immunereprogramming of the glial scar. In addition, the in situ forming capabilities of HAMC hydrogels and minimal swelling following gelation make them ideally suited for chronic stroke applications [9]. In addition, their physical properties and biodegradability are optimised to ensure they mimic the elasticity of neuronal tissue and undergo controlled degradation and resorption in the months following implantation.…”

“…Hydrogels are emerging as a platform to improve regenerative payload delivery due to their unique physicochemical properties that are tuneable to the tissue type required for site-specific delivery [8][9]. These biomaterial technologies are manufactured from natural or synthetic polymer solutions that are induced to undergo solution-gel transition using chemical, physical or thermal triggers to yield three-dimensional water-based hydrogels.…”

Modulating neuroinflammation through molecular, cellular and biomaterial‐based approaches to treat spinal cord injury

“…To tackle the challenges in drug delivery to the injured spinal cord, noninvasive strategies utilizing drug-loaded nanoparticles have been developed to overcome the BSCB. [166][167][168] In recent years, nanoparticles with neuroinflammation-targeting designs allowed more targeted delivery and had led to better recovery. 169,170 On the other hand, although it is more invasive, delivering the drugs in situ can bypass the BSCB and reach the injured site directly.…”

Clickable Biomaterials for Modulating Neuroinflammation

“…Biomaterials have been used for prophylactic vaccines [ 90 ], cancer therapy [ 91 , 92 ], treating autoimmune diseases like diabetes [ 93 ], and promoting tissue regeneration [ 94 , 95 , 96 ]. We briefly review a few notable examples, but further review of CNS-specific or biomaterial-based immunomodulation is available [ 10 , 18 , 97 , 98 , 99 , 100 , 101 , 102 , 103 ].…”