Concentration-dependent rheological properties of ECM hydrogel for intracerebral delivery to a stroke cavity

Abstract

Biomaterials composed of mammalian extracellular matrix (ECM) promote constructive tissue remodeling with minimal scar tissue formation in many anatomical sites. However, the optimal shape and form of ECM scaffold for each clinical application can vary markedly. ECM hydrogels have been shown to promote chemotaxis and differentiation of neuronal stem cells, but minimally invasive delivery of such scaffold materials to the central nervous system (CNS) would require an injectable form. These ECM materials can be manufactured to exist in fluid phase at room temperature, while forming hydrogels at body temperature in a concentration-dependent fashion. Implantation into the lesion cavity after a stroke could hence provide a means to support endogenous repair mechanisms. Herein, we characterize the rheological properties of an ECM hydrogel composed of urinary bladder matrix (UBM) that influence its delivery and in vivo interaction with host tissue. There was a notable concentration-dependence in viscosity, stiffness, and elasticity; all characteristics important for minimally invasive intracerebral delivery. An efficient MRI-guided injection with drainage of fluid from the cavity is described to assess in situ hydrogel formation and ECM retention at different concentrations (0, 1, 2, 3, 4, and 8 mg/mL). Only ECM concentrations >3 mg/mL gelled within the stroke cavity. Lower concentrations were not retained within the cavity, but extensive permeation of the liquid phase ECM into the peri-infarct area was evident. The concentration of ECM hydrogel is hence an important factor affecting gelation, host-biomaterial interface, as well intra-lesion distribution.

Effects of Neural Stem Cell and Olfactory Ensheathing Cell Co-transplants on Tissue Remodelling After Transient Focal Cerebral Ischemia in the Adult Rat

“…This specific model is well-characterized in the literature and has been used in a number of experimental studies of transient focal cerebral ischemia, including studies investigating intrastriatal stem cell transplantation [7,[49][50][51][52]. However, one challenge associated with the MCAo model is that it is known to result in lesions of variable severity [7,[52][53][54]. While this per se may be considered positive in terms of the extent to which the MCAo model can recapitulate the variability observed in stroke patients, such differences in lesion severity, coupled to the strict criteria which were applied for the inclusion of lesioned animals in the study, did result in relatively small group sizes.…”

“…Notwithstanding that the variability of lesion pathology between subjects in a given cohort post-MCAo may confound a thorough elucidation of the exact mechanisms involved, it is worth considering how future strategies for stroke repair may involve OECs as part of an in situ tissue engineering paradigm as an alternative to or in combination with other approaches, as for example tailored biomaterials [6,7,53,55].…”

An update on stem cell therapy for neurological disorders: cell death pathways as therapeutic targets

“…The authors have conducted previous studies that prove the efficacy of hydrogels in the treatment of stroke. In an earlier study, they addressed the particular structure-function relationship of biomaterials and the necessity for testing and confirming the existence of an injectable form [16]. In a recent study, they tested the use of an acellular extracellular matrix in encouraging the infiltration of host brain cells and replacing necrotic debris.…”

Biomaterial applications in neural therapy and repair

“…Crosslinking of water soluble polymers produces a hydrogel that has excellent nutrient and oxygen permeability, promoting cell survival inside the scaffold [51]. These biomaterials can be formulated to exist in liquid state at room temperature while forming gels in situ, allowing for minimal invasive delivery through small-gauge needles using MRI guidance [52]. For example, collagen, methylcellulose, and agarose are all temperature sensitive polymers and their gelation rates can easily be controlled by adding other natural polymers such as hyaluronic acid [53].…”

“…The high water content of hydrogels makes them very biocompatible and promising candidates for tissue engineering applications. It is an important consideration that large volume of hydrogel injection into the lesion cavity or into the peri-infarct area would cause tissue disruption and increased intracerebral pressure [54,55], and therefore an innovating neurosurgical technique that allows for the drainage of ECF should be employed to avoid additional damage [52].…”