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2023

Engineered neural tissue made using hydrogels derived from decellularised tissues for the regeneration of peripheral nerves

S. C. Kellaway, V. Roberton, J. N. Jones, R. Loczenski, J. B. Phillips, L. J. White
DOI: 10.1016/j.actbio.2022.12.003

Engineered neural tissue (EngNT) promotes in vivo axonal regeneration. Decellularised materials (dECM) are complex biologic scaffolds that can improve the cellular environment and also encourage positive tissue remodelling in vivo. We hypothesised that we could incorporate a hydrogel derived from a decellularised tissue (dECMh) into EngNT, thereby providing an alternative to the currently used purified collagen I hydrogel for the first time. Decellularisation was carried out on bone (B-ECM), liver (LIV-ECM), and small intestinal (SIS-ECM) tissues and the resultant dECM was biochemically and mechanically characterised. dECMh differed in mechanical and biochemical properties that likely had an effect on Schwann cell behaviour observed in metabolic activity and contraction profiles. Cellular alignment was observed in tethered moulds within the B-ECM and SIS-ECM derived hydrogels only. No difference was observed in dorsal root ganglia (DRG) neurite extension between the dECMh groups and collagen I groups when applied as a coverslip coating, however, when DRG were seeded atop EngNT constructs, only the B-ECM derived EngNT performed similarly to collagen I derived EngNT. B-ECM EngNT further exhibited similar axonal regeneration to collagen I EngNT in a 10 mm gap rat sciatic nerve injury model after 4 weeks. Our results have shown that various dECMh can be utilised to produce EngNT that can promote neurite extension in vitro and axonal regeneration in vivo.
Liver
,
Smart Materials

Peptide-protein co-assemblies into hierarchical and bioactive tubular membranes

A. Majkowska, K.E. Inostroza-Brito, M. Gonzalez, C. Redondo-Gomez, A. Rice, J.C. Rodriguez-Cabello, A.E. Del Rio Hernandez, A Mata
DOI:10.1021/acs.biomac.2c01095

Multicomponent self-assembly offers opportunities for the design of complex and functional biomaterials with tunable properties. Here, we demonstrate how minor modifications in the molecular structures of peptide amphiphiles (PAs) and elastin-like recombinamers (ELs) can be used to generate coassembling tubular membranes with distinct structures, properties, and bioactivity. First, by introducing minor modifications in the charge density of PA molecules (PAK2, PAK3, PAK4), different diffusion-reaction processes can be triggered, resulting in distinct membrane microstructures. Second, by combining different types of these PAs prior to their coassembly with ELs, further modifications can be achieved, tuning the structures and properties of the tubular membranes. Finally, by introducing the cell adhesive peptide RGDS in either the PA or EL molecules, it is possible to harness the different diffusion-reaction processes to generate tubular membranes with distinct bioactivities. The study demonstrates the possibility to trigger and achieve minor but crucial differences in coassembling processes and tune material structure and bioactivity. The study demonstrates the possibility to use minor, yet crucial, differences in coassembling processes to tune material structure and bioactivity.
Musculoskeletal
,
Smart Materials

Material-driven fibronectin and vitronectin assembly enhances BMP-2 presentation and osteogenesis

Y. Xiao, H. Donnelly, M. Sprott, J. Luo, V. Jayawarna, L. Lemgruber, P. M. Tsimbouri, R.M.D. Meek, M. Salmeron-Sanchez, M. J. Dalby
DOI: 10.1016/j.mtbio.2022.100367

Mesenchymal stem cell (MSC)-based tissue engineering strategies are of interest in the field of bone tissue regenerative medicine. MSCs are commonly investigated in combination with growth factors (GFs) and biomaterials to provide a regenerative environment for the cells. However, optimizing how biomaterials interact with MSCs and efficiently deliver GFs, remains a challenge. Here, via plasma polymerization, tissue culture plates are coated with a layer of poly (ethyl acrylate) (PEA), which is able to spontaneously permit fibronectin (FN) to form fibrillar nanonetworks. However, vitronectin (VN), another important extracellular matrix (ECM) protein forms multimeric globules on the polymer, thus not displaying functional groups to cells. Interestingly, when FN and VN are co-absorbed onto PEA surfaces, VN can be entrapped within the FN fibrillar nanonetwork in the monomeric form providing a heterogeneous, open ECM network. The combination of FN and VN promote MSC adhesion and leads to enhanced GF binding; here we demonstrate this with bone morphogenetic protein-2 (BMP2). Moreover, MSC differentiation into osteoblasts is enhanced, with elevated expression of osteopontin (OPN) and osteocalcin (OCN) quantified by immunostaining, and increased mineralization observed by von Kossa staining. Osteogenic intracellular signalling is also induced, with increased activity in the SMAD pathway. The study emphasizes the need of recapitulating the complexity of native ECM to achieve optimal cell-material interactions.
Musculoskeletal
,
Smart Materials

STING agonist delivery by tumour-penetrating PEG-lipid nanodiscs primes robust anticancer immunity

E.L. Dane, A. Belessiotis-Richards, C. Backlund, J. Wang, K. Hidaka, L.E. Milling, S. Bhagchandani, M.B. Melo, S. Wu, N. Li, N. Donahue, K. Ni, L. Ma, M. Okaniwa, M.M. Stevens, A. Alexander-Katz, D.J. Irvine
DOI: 10.1038/s41563-022-01251-z

Activation of the innate immune STimulator of INterferon Genes (STING) pathway potentiates antitumour immunity, but systemic delivery of STING agonists to tumours is challenging. We conjugated STING-activating cyclic dinucleotides (CDNs) to PEGylated lipids (CDN-PEG-lipids; PEG, polyethylene glycol) via a cleavable linker and incorporated them into lipid nanodiscs (LNDs), which are discoid nanoparticles formed by self-assembly. Compared to state-of-the-art liposomes, intravenously administered LNDs carrying CDN-PEG-lipid (LND-CDNs) exhibited more efficient penetration of tumours, exposing the majority of tumour cells to STING agonist. A single dose of LND-CDNs induced rejection of established tumours, coincident with immune memory against tumour rechallenge. Although CDNs were not directly tumoricidal, LND-CDN uptake by cancer cells correlated with robust T-cell activation by promoting CDN and tumour antigen co-localization in dendritic cells. LNDs thus appear promising as a vehicle for robust delivery of compounds throughout solid tumours, which can be exploited for enhanced immunotherapy.
Smart Materials

Polysaccharide-Polyplex Nanofilm Coatings Enhance Nanoneedle-Based Gene Delivery and Transfection Efficiency

D. Hachim, J. Zhao, J. Bhankharia, R. Nuñez-Toldra, L. Brito, H. Seong, M. Becce, L. Ouyang, C.L. Grigsby, S.G. Higgins, C.M. Terracciano, M.M. Stevens
DOI: 10.1002/smll.202202303

Non-viral vectors represent versatile and immunologically safer alternatives for nucleic acid delivery. Nanoneedles and high-aspect ratio nanostructures are unconventional but interesting delivery systems, in which delivery is mediated by surface interactions. Herein, nanoneedles are synergistically combined with polysaccharide-polyplex nanofilms and enhanced transfection efficiency is observed, compared to polyplexes in suspension. Different polyplex-polyelectrolyte nanofilm combinations are assessed and it is found that transfection efficiency is enhanced when using polysaccharide-based polyanions, rather than being only specific for hyaluronic acid, as suggested in earlier studies. Moreover, results show that enhanced transfection is not mediated by interactions with the CD44 receptor, previously hypothesized as a major mechanism mediating enhancement via hyaluronate. In cardiac tissue, nanoneedles are shown to increase the transfection efficiency of nanofilms compared to flat substrates; while in vitro, high transfection efficiencies are observed in nanostructures where cells present large interfacing areas with the substrate. The results of this study demonstrate that surface-mediated transfection using this system is efficient and safe, requiring amounts of nucleic acid with an order of magnitude lower than standard culture transfection. These findings expand the spectrum of possible polyelectrolyte combinations that can be used for the development of suitable non-viral vectors for exploration in further clinical trials.
Smart Materials

Tissue Engineering Cartilage with Deep Zone Cytoarchitecture by High-Resolution Acoustic Cell Patterning

J.P.K. Armstrong, E. Pchelintseva, S. Treumuth, C. Campanella, C. Meinert, T.J. Klein, D.W. Hutmacher, B.W. Drinkwater, M.M. Stevens
DOI: 10.1002/adhm.202200481

The ultimate objective of tissue engineering is to fabricate artificial living constructs with a structural organization and function that faithfully resembles their native tissue counterparts. For example, the deep zone of articular cartilage possesses a distinctive anisotropic architecture with chondrocytes organized in aligned arrays ≈1–2 cells wide, features that are oriented parallel to surrounding extracellular matrix fibers and orthogonal to the underlying subchondral bone. Although there are major advances in fabricating custom tissue architectures, it remains a significant technical challenge to precisely recreate such fine cellular features in vitro. Here, it is shown that ultrasound standing waves can be used to remotely organize living chondrocytes into high-resolution anisotropic arrays, distributed throughout the full volume of agarose hydrogels. It is demonstrated that this cytoarchitecture is maintained throughout a five-week course of in vitro tissue engineering, producing hyaline cartilage with cellular and extracellular matrix organization analogous to the deep zone of native articular cartilage. It is anticipated that this acoustic cell patterning method will provide unprecedented opportunities to interrogate in vitro the contribution of chondrocyte organization to the development of aligned extracellular matrix fibers, and ultimately, the design of new mechanically anisotropic tissue grafts for articular cartilage regeneration.
Musculoskeletal
,
Smart Materials

Gelatin Methacryloyl Hydrogels for Musculoskeletal Tissue Regeneration

Y. Kim, J. Dawson, R.O.C. Oreffo, Y. Tabata, D. Kumar, C. Aparicio, I. Mutreja
DOI: 10.3390/bioengineering9070332

Musculoskeletal disorders are a significant burden on the global economy and public health. Hydrogels have significant potential for enhancing the repair of damaged and injured musculoskeletal tissues as cell or drug delivery systems. Hydrogels have unique physicochemical properties which make them promising platforms for controlling cell functions. Gelatin methacryloyl (GelMA) hydrogel in particular has been extensively investigated as a promising biomaterial due to its tuneable and beneficial properties and has been widely used in different biomedical applications. In this review, a detailed overview of GelMA synthesis, hydrogel design and applications in regenerative medicine is provided. After summarising recent progress in hydrogels more broadly, we highlight recent advances of GelMA hydrogels in the emerging fields of musculoskeletal drug delivery, involving therapeutic drugs (e.g., growth factors, antimicrobial molecules, immunomodulatory drugs and cells), delivery approaches (e.g., single-, dual-release system), and material design (e.g., addition of organic or inorganic materials, 3D printing). The review concludes with future perspectives and associated challenges for developing local drug delivery for musculoskeletal applications.
Musculoskeletal
,
Smart Materials

Modelling skeletal pain harnessing tissue engineering

L. Iafrate, M. Benedetti, S. Donsante, A. Rosa, A. Corsi, R.O.C. Oreffo, M. Riminucci, G. Ruocco, C. Scognamiglio, G. Cidonio
DOI: 10.1007/s44164-022-00028-7

Bone pain typically occurs immediately following skeletal damage with mechanical distortion or rupture of nociceptive fibres. The pain mechanism is also associated with chronic pain conditions where the healing process is impaired. Any load impacting on the area of the fractured bone will stimulate the nociceptive response, necessitating rapid clinical intervention to relieve pain associated with the bone damage and appropriate mitigation of any processes involved with the loss of bone mass, muscle, and mobility and to prevent death. The following review has examined the mechanisms of pain associated with trauma or cancer-related skeletal damage focusing on new approaches for the development of innovative therapeutic interventions. In particular, the review highlights tissue engineering approaches that offer considerable promise in the application of functional biomimetic fabrication of bone and nerve tissues. The strategic combination of bone and nerve tissue engineered models provides significant potential to develop a new class of in vitro platforms, capable of replacing in vivo models and testing the safety and efficacy of novel drug treatments aimed at the resolution of bone-associated pain. To date, the field of bone pain research has centred on animal models, with a paucity of data correlating to the human physiological response. This review explores the evident gap in pain drug development research and suggests a step change in approach to harness tissue engineering technologies to recapitulate the complex pathophysiological environment of the damaged bone tissue enabling evaluation of the associated pain-mimicking mechanism with significant therapeutic potential therein for improved patient quality of life.
Musculoskeletal
,
Smart Materials

Advancing Our Understanding of the Chronically Denervated Schwann Cell: A Potential Therapeutic Target?

L. McMorrow, A. Kosalko, D. Robinson, A. Saiani, A. J. Reid
DOI: 10.3390/biom12081128

Outcomes for patients following major peripheral nerve injury are extremely poor. Despite advanced microsurgical techniques, the recovery of function is limited by an inherently slow rate of axonal regeneration. In particular, a time-dependent deterioration in the ability of the distal stump to support axonal growth is a major determinant to the failure of reinnervation. Schwann cells (SC) are crucial in the orchestration of nerve regeneration; their plasticity permits the adoption of a repair phenotype following nerve injury. The repair SC modulates the initial immune response, directs myelin clearance, provides neurotrophic support and remodels the distal nerve. These functions are critical for regeneration; yet the repair phenotype is unstable in the setting of chronic denervation. This phenotypic instability accounts for the deteriorating regenerative support offered by the distal nerve stump. Over the past 10 years, our understanding of the cellular machinery behind this repair phenotype, in particular the role of c-Jun, has increased exponentially, creating opportunities for therapeutic intervention. This review will cover the activation of the repair phenotype in SC, the effects of chronic denervation on SC and current strategies to 'hack' these cellular pathways toward supporting more prolonged periods of neural regeneration.
Smart Materials

Rapid fabrication and screening of tailored functional 3D biomaterials: Validation in bone tissue repair – Part II

A. Conde-Gonzalez, M. Glinka, D. Dutta, R. Wallace, A. Callanan, R.O.C. Oreffo, M. Bradley
DOI:10.1016/j.bioadv.2022.213250

Regenerative medicine strategies place increasingly sophisticated demands on 3D biomaterials to promote tissue formation at sites where tissue would otherwise not form. Ideally, the discovery/fabrication of the 3D scaffolds needs to be high-throughput and uniform to ensure quick and in-depth analysis in order to pinpoint appropriate chemical and mechanical properties of a biomaterial. Herein we present a versatile technique to screen new potential biocompatible acrylate-based 3D scaffolds with the ultimate aim of application in tissue repair. As part of this process, we identified an acrylate-based 3D porous scaffold that promoted cell proliferation followed by accelerated tissue formation, pre-requisites for tissue repair. Scaffolds were fabricated by a facile freeze-casting and an in-situ photo-polymerization route, embracing a high-throughput synthesis, screening and characterization protocol. The current studies demonstrate the dependence of cellular growth and vascularization on the porosity and intrinsic chemical nature of the scaffolds, with tuneable 3D scaffolds generated with large, interconnected pores suitable for cellular growth applied to skeletal reparation. Our studies showed increased cell proliferation, collagen and ALP expression, while chorioallantoic membrane assays indicated biocompatibility and demonstrated the angiogenic nature of the scaffolds. VEGRF2 expression in vivo observed throughout the 3D scaffolds in the absence of growth factor supplementation demonstrates a potential for angiogenesis. This novel platform provides an innovative approach to 3D scanning of synthetic biomaterials for tissue regeneration.
Musculoskeletal
,
Smart Materials

2022

Current insights into the bone marrow niche: From biology in vivo to bioengineering ex vivo

Y. Xiao, C.S. McGuinness, W.S. Doherty-Boyd, M. Salmeron-Sanchez, H. Donnelly, M.J. Dalby
Biomaterials, 2022, PMID: 35580474. https://doi.org/10.1016/j.biomaterials.2022.121568
Musculoskeletal
,
Smart Materials

Living Biointerfaces for the Maintenance of Mesenchymal Stem Cell Phenotypes

M. Petaroudi, A. Rodrigo-Navarro, O. Dobre, M. J. Dalby, M. Salmeron-Sanchez
Advanced Functional Materials, 2022, https://doi.org/10.1002/adfm.202203352
Musculoskeletal
,
Smart Materials

From hurdle to springboard: The macrophage as target in biomaterial-based bone regeneration strategies

Y.H. Kim, R.O.C. Oreffo, J.I. Dawson
Bone, 2022, Jun;159:116389. https://doi.org/10.1016/j.bone.2022.116389
Musculoskeletal
,
Smart Materials

Mineralizing coating on 3D printed scaffolds for enhanced osseo-integration

A. Hasan, R.Bagnol, R. Owen, A. Latif, H.M. Rostam, S. Elsharkawy, F. Rose, J.C. Rodriguez-Cabello, A.M. Ghaemmaghami, D. Eglin, and A. Mata
Frontiers in Bioengineering and Biotechnology, 2022, p.810. https://doi.org/10.3389/fbioe.2022.836386
Musculoskeletal
,
Smart Materials

Rational design of hydrogels for immunomodulation

W. Bu, Y. Wu, A.M. Ghaemmaghami, H. Sun, A. Mata
Regenerative Biomaterials, 2022, https://doi.org/10.1093/rb/rbac009.
Smart Materials

Embracing complexity in biomaterials design

H.S. Azevedo and A. Mata A
Biomaterials and Biosystems, 2022, https://doi.org/10.1016/j.bbiosy.2022.100039
Smart Materials

Exploiting the fundamental of biological organization for the advancement of biofabrication

J. Hill, R. Wildman, A. Mata
Current Opinion in Biotechnology, 2022, https://doi.org/10.1016/j.copbio.2021.10.016
Smart Materials

Disinfector-assisted low temperature reduced graphene oxide-protein surgical dressing for the postoperative photothermal treatment of melanoma

Y. Wu, J. Yang, A. van Teijlingen, A. Berardo, I. Corridori, J. Feng, J. Xu, M.M. Titirici, J.C. Rodriguez-Cabello, N.M. Pugno, J. Sun, W. Wang, A. Mata
Advanced Functional Materials, 2022, https://doi.org/10.1002/adfm.202205802
Smart Materials

Self-assembling, peptide hydrogels as functional tools to tackle intervertebral disc degeneration

C. Ligorio, J.A. Hoyland, A. Saiani
Gels, 2022, 8(4):211, https://doi.org/10.3390/gels8040211
Smart Materials

Acidic and basic self-assembling peptide and peptide-graphene oxide hydrogels: characterisation and effect on encapsulated nucleus pulposus cells

C. Ligorio, A. Vijayaraghavan, J.A. Hoyland, A. Saiani
Acta Biomaterialia, 2022,143: 145-158, https://doi.org/10.1016/j.actbio.2022.02.022
Smart Materials

In vitro and in vivo investigation of a zonal microstructured scaffold for osteochondral defect repair

J.A.M. Steele, A.C. Moore, J.S. Pierre, …, M.M. Stevens
Biomaterials, 2022, 286:121548, https://doi.org/10.1016/j.biomaterials.2022.121548
Smart Materials

Design and clinical application of injectable hydrogels for musculoskeletal therapy

Ø. Øvrebø, G. Perale, J.P. Wojciechowski, C. Echalier, J.R.T. Jeffers, M.M. Stevens, H.J. Haugen, F. Rossi
Bioengineering and Translational Medicine, 2022, ISSN:2380-6761f, https://doi.org/10.1002/btm2.10295
Smart Materials

Tunable Microgel-Templated Porogel (MTP) Bioink for 3D Bioprinting Applications

L. Ouyang, J.P. Wojciechowski, J. Tang, Y. Guo, M.M. Stevens
Advanced Healthcare Materials, 2022, ISSN:2192-2640, https://doi.org/10.1002/adhm.202200027
Smart Materials

Modeling the tumor microenvironment of ovarian cancer: the application of self-assembling biomaterials

A.K. Mendoza-Martinez, D. Loessner, A. Mata, H.S. Azevedo
Cancers, 2022, https://doi.org/10.3390/cancers13225745
Smart Materials

Exploiting the fundamentals of biological organization for the advancement of biofabrication

J. Hill, R. Wildman, A. Mata
Current Opinion in Biotechnology, 2022, https://doi.org/10.1016/j.copbio.2021.10.016
Smart Materials

2021

Early development of a polycaprolactone electrospun augment for anterior cruciate ligament reconstruction

L. Savic, E.M. Augustyniak, A. Kastensson, S. Snelling, R.E. Abhari, M. Baldwin, A. Price, W. Jackson, A. Carr, P.A. Mouthuy
Materials Science Engineering: C Materials for Biological Applications, 2021, doi: 10.1016/j.msec.2021.112414
Smart Materials

2020

A blueprint for translational regenerative medicine,

Armstrong JPK, Keane TJ, Roques AC, Stephen Patrick P, Mooney CM, Kuan W-L, Pisupati V, Oreffo ROC, Stuckey D, Watt FM, Forbes SJ, Barker RA, Stevens M.
Science Translational Medicine 02 Dec 2020, Vol. 12, Issue 572,
DOI: 10.1126/scitranslmed.aaz2253
Engineered cell environment
,
Pluripotent stem cells and engineered cells
,
Smart Materials

2017

SPIONs for cell labelling and tracking using MRI: magnetite or maghemite?

Barrow M, Taylor A, Fuentes-Caparrós AM, Sharkey J, Daniels LM, Mandal P, Park BK, Murray P, Rosseinsky MJ, Adams DJ.
Biomater Sci. 2017 Dec 19;6(1):101-106.
doi: 10.1039/c7bm00515f.
Smart Materials

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