TISSUE DECELLULARIZATION METHODS

Provided herein are methods of producing an acellular tissue product wherein the method can include the step of inducing apoptosis and washing the tissue after induction of apoptosis with a tonic solution. Also provided herein are acellular tissue products produced by the methods provided herein and methods of administering the acellular tissue products to a subject in need thereof

Applicability of Drug Response Metrics for Cancer Studies using Biomaterials

Bioengineers have built models of the tumour microenvironment (TME) in which to study cell–cell interactions, mechanisms of cancer growth and metastasis, and to test new therapies. These models allow researchers to culture cells in conditions that include features of the in vivo TME implicated in regulating cancer progression, such as extracellular matrix (ECM) stiffness, integrin binding to the ECM, immune and stromal cells, growth factor and cytokine depots, and a three-dimensional geometry more representative of the in vivo TME than tissue culture polystyrene (TCPS). These biomaterials could be particularly useful for drug screening applications to make better predictions of efficacy, offering better translation to preclinical models and clinical trials. However, it can be challenging to compare drug response reports across different biomaterial platforms in the current literature. This is, in part, a result of inconsistent reporting and improper use of drug response metrics, and vast differences in cell growth rates across a large variety of biomaterial designs. This study attempts to clarify the definitions of drug response measurements used in the field, and presents examples in which these measurements can and cannot be applied. We suggest as best practice to measure the growth rate of cells in the absence of drug, and follow our ‘decision tree’ when reporting drug response metrics

An injectable acellular nerve graft as a platform for treating spinal cord injury

textSpinal cord injury (SCI) affects a quarter million people in the US, and there is currently no clinical treatment option. Approximately 60% of clinical SCI results from spinal cord contusion, which causes formation of a growth-inhibitory cavity. Research with experimental SCI models has shown spinal axons can regenerate despite this cavity if supplied with appropriate conditions. Two strategies have proven particularly successful: grafting segments of peripheral nervous tissue and transplanting pro-regenerative cells such as peripheral nerve Schwann cells. While implanting fresh nerve tissue risks immune rejection, this challenge can be overcome by removing immunogenic tissue components through decellularization. Unfortunately, decellularization also eliminates the benefits of resident nerve Schwann cells, and transplanting purified Schwann cells after SCI requires the addition of a scaffold for effective cell survival. Tumor-derived Matrigel is often used experimentally to support Schwann cell therapy. For successful translation into humans, however, more clinically-relevant alternatives are needed. Acellular nerve grafts are currently available clinically for peripheral nerve repair and therefore have potential to be such an alternative, although they require some modification to be compatible with contusion injury. Contusion cavities necessitate scaffolds be applied using minimally-invasive techniques such as injection. Additionally, injectable scaffold are easier to incorporate with other therapeutics such as cells. The goal of this dissertation was to develop and evaluate an injectable acellular nerve graft as a potential intervention for treating contusion SCI. This thermally-gelling nerve scaffold was shown to approximate the chemical composition of native nerve tissue and was optimized to match the mechanical properties of rat neural tissue. Injectable nerve scaffolds were biocompatible with Schwann cells in vitro and promoted a regenerative immune response in vivo in a rat model of cervical contusion SCI. Delivery of injectable nerve alone supported axon growth into and beyond the SCI lesion after 8 weeks. In collaboration with Dr. Mary Bunge at the Miami Institute to Cure Paralysis, transplanting Schwann cells in injectable nerve promoted equivalent yet faster recovery compared to using Matrigel. This injectable acellular nerve graft is therefore a clinically-relevant alternative to Matrigel for enhancing Schwann cell therapy and promoting recovery following traumatic SCI.Chemical Engineerin

Clickable Biomaterials for Modulating Neuroinflammation

Crosstalk between the nervous and immune systems in the context of trauma or disease can lead to a state of neuroinflammation or excessive recruitment and activation of peripheral and central immune cells. Neuroinflammation is an underlying and contributing factor to myriad neuropathologies including neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease; autoimmune diseases like multiple sclerosis; peripheral and central nervous system infections; and ischemic and traumatic neural injuries. Therapeutic modulation of immune cell function is an emerging strategy to quell neuroinflammation and promote tissue homeostasis and/or repair. One such branch of ‘immunomodulation’ leverages the versatility of biomaterials to regulate immune cell phenotypes through direct cell-material interactions or targeted release of therapeutic payloads. In this regard, a growing trend in biomaterial science is the functionalization of materials using chemistries that do not interfere with biological processes, so-called ‘click’ or bioorthogonal reactions. Bioorthogonal chemistries such as Michael-type additions, thiol-ene reactions, and Diels-Alder reactions are highly specific and can be used in the presence of live cells for material crosslinking, decoration, protein or cell targeting, and spatiotemporal modification. Hence, click-based biomaterials can be highly bioactive and instruct a variety of cellular functions, even within the context of neuroinflammation. This manuscript will review recent advances in the application of click-based biomaterials for treating neuroinflammation and promoting neural tissue repair

Perspective on Translating Biomaterials Into Glioma Therapy: Lessons From in Vitro Models

Glioblastoma (GBM) is the most common and malignant form of brain cancer. Even with aggressive standard of care, GBM almost always recurs because its diffuse, infiltrative nature makes these tumors difficult to treat. The use of biomaterials is one strategy that has been, and is being, employed to study and overcome recurrence. Biomaterials have been used in GBM in two ways: in vitro as mediums in which to model the tumor microenvironment, and in vivo to sustain release of cytotoxic therapeutics. In vitro systems are a useful platform for studying the effects of drugs and tissue-level effectors on tumor cells in a physiologically relevant context. These systems have aided examination of how glioma cells respond to a variety of natural, synthetic, and semi-synthetic biomaterials with varying substrate properties, biochemical factor presentations, and non-malignant parenchymal cell compositions in both 2D and 3D environments. The current in vivo paradigm is completely different, however. Polymeric implants are simply used to line the post-surgical resection cavities and deliver secondary therapies, offering moderate impacts on survival. Instead, perhaps we can use the data generated from in vitro systems to design novel biomaterial-based treatments for GBM akin to a tissue engineering approach. Here we offer our perspective on the topic, summarizing how biomaterials have been used to identify facets of glioma biology in vitro and discussing the elements that show promise for translating these systems in vivo as new therapies for GBM

Applicability of Drug Response Metrics for Cancer Studies Using Biomaterials

Bioengineers have built models of the tumour microenvironment (TME) in which to study cell–cell interactions, mechanisms of cancer growth and metastasis, and to test new therapies. These models allow researchers to culture cells in conditions that include features of the in vivo TME implicated in regulating cancer progression, such as extracellular matrix (ECM) stiffness, integrin binding to the ECM, immune and stromal cells, growth factor and cytokine depots, and a three-dimensional geometry more representative of the in vivo TME than tissue culture polystyrene (TCPS). These biomaterials could be particularly useful for drug screening applications to make better predictions of efficacy, offering better translation to preclinical models and clinical trials. However, it can be challenging to compare drug response reports across different biomaterial platforms in the current literature. This is, in part, a result of inconsistent reporting and improper use of drug response metrics, and vast differences in cell growth rates across a large variety of biomaterial designs. This study attempts to clarify the definitions of drug response measurements used in the field, and presents examples in which these measurements can and cannot be applied. We suggest as best practice to measure the growth rate of cells in the absence of drug, and follow our ‘decision tree’ when reporting drug response metrics