In vitro neuronal and glial response to magnetically stimulated piezoelectric poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV)/cobalt ferrite (CFO) microspheres.

Polymer biomaterials are being considered for tissue regeneration due to the possibility of resembling different extracellular matrix characteristics. However, most current scaffolds cannot respond to physical-chemical modifications of the cell microenvironment. Stimuli-responsive materials, such as electroactive smart polymers, are increasingly gaining attention once they can produce electrical potentials without external power supplies. The presence of piezoelectricity in human tissues like cartilage and bone highlights the importance of electrical stimulation in physiological conditions. Although poly(vinylidene fluoride) (PVDF) is one of the piezoelectric polymers with the highest piezoelectric response, it is not biodegradable. Poly(hydroxybutyrate-co-hydroxyvalerate) (PHBV) is a promising copolymer of poly(hydroxybutyrate) (PHB) for tissue engineering and regeneration applications. It offers biodegradability, piezoelectric properties, biocompatibility, and bioactivity, making it a superior option to PVDF for biomedical purposes requiring biodegradability. Magnetoelectric polymer composites can be made by combining magnetostrictive particles and piezoelectric polymers to further tune their properties for tissue regeneration. These composites convert magnetic stimuli into electrical stimuli, generating local electrical potentials for various applications. Cobalt ferrites (CFO) and piezoelectric polymers have been combined and processed into different morphologies, maintaining biocompatibility for tissue engineering. The present work studied how PHBV/CFO microspheres affected neural and glial response in spinal cord cultures. It is expected that the electrical signals generated by these microspheres due to their magnetoelectric nature could aid in tissue regeneration and repair. PHBV/CFO microspheres were not cytotoxic and were able to impact neurite outgrowth and promote neuronal differentiation. Furthermore, PHBV/CFO microspheres led to microglia activation and induced the release of several bioactive molecules. Importantly, magnetically stimulated microspheres ameliorated cell viability after an in vitro ROS-induced lesion of spinal cord cultures, which suggests a beneficial effect on tissue regeneration and repair.

Enhanced neuronal differentiation by dynamic piezoelectric stimulation.

Electroactive smart materials play an important role for tissue regenerative applications. Poly(vinylidene fluoride) (PVDF) is a specific subtype of piezoelectric electroactive material that generates electrical potential upon mechanical stimulation. This work focuses on the application of piezoelectric PVDF films for neural differentiation. Human neural precursor cells (hNPCs) are cultured on piezoelectric poled and non-poled ß-PVDF films with or without a pre-coating step of poly-d-lysine and laminin (PDL/L). Subsequently, hNPCs differentiation into the neuronal lineage is assessed (MAP2+ and DCX+ ) under static or dynamic (piezoelectric stimulation) culture conditions. The results demonstrate that poled and coated ß-PVDF films induce neuronal differentiation under static culture conditions which is further enhanced with mechanical stimulation. In silico calculations of the electrostatic potential of different domains of laminin, highlight the high polarity of those domains, which shows a clear preference to interact with the varying surface electric field of the piezoelectric material under mechanical stimulation. These interactions might explain the higher neuronal differentiation induced by poled ß-PVDF films pre-coated with PDL/L under dynamic conditions. Our results suggest that electromechanical stimuli, such as the ones induced by piezoelectric ß-PVDF films, are suitable to promote neuronal differentiation and hold great promise for the development of neuroregenerative therapies.

Mussel-Inspired Catechol Functionalisation as a Strategy to Enhance Biomaterial Adhesion: A Systematic Review.

Biomaterials have long been explored in regenerative medicine strategies for the repair or replacement of damaged organs and tissues, due to their biocompatibility, versatile physicochemical properties and tuneable mechanical cues capable of matching those of native tissues. However, poor adhesion under wet conditions (such as those found in tissues) has thus far limited their wider application. Indeed, despite its favourable physicochemical properties, facile gelation and biocompatibility, gellan gum (GG)-based hydrogels lack the tissue adhesiveness required for effective clinical use. Aiming at assessing whether substitution of GG by dopamine (DA) could be a suitable approach to overcome this problem, database searches were conducted on PubMed® and Embase® up to 2 March 2021, for studies using biomaterials covalently modified with a catechol-containing substituent conferring improved adhesion properties. In this regard, a total of 47 reports (out of 700 manuscripts, ~6.7%) were found to comply with the search/selection criteria, the majority of which (34/47, ~72%) were describing the modification of natural polymers, such as chitosan (11/47, ~23%) and hyaluronic acid (6/47, ~13%); conjugation of dopamine (as catechol "donor") via carbodiimide coupling chemistry was also predominant. Importantly, modification with DA did not impact the biocompatibility and mechanical properties of the biomaterials and resulting hydrogels. Overall, there is ample evidence in the literature that the bioinspired substitution of polymers of natural and synthetic origin by DA or other catechol moieties greatly improves adhesion to biological tissues (and other inorganic surfaces).

Electroactive Smart Materials for Neural Tissue Regeneration.

Repair in the human nervous system is a complex and intertwined process that offers significant challenges to its study and comprehension. Taking advantage of the progress in fields such as tissue engineering and regenerative medicine, the scientific community has witnessed a strong increase of biomaterial-based approaches for neural tissue regenerative therapies. Electroactive materials, increasingly being used as sensors and actuators, also find application in neurosciences due to their ability to deliver electrical signals to the cells and tissues. The use of electrical signals for repairing impaired neural tissue therefore presents an interesting and innovative approach to bridge the gap between fundamental research and clinical applications in the next few years. In this review, first a general overview of electroactive materials, their historical origin, and characteristics are presented. Then a comprehensive view of the applications of electroactive smart materials for neural tissue regeneration is presented, with particular focus on the context of spinal cord injury and brain repair. Finally, the major challenges of the field are discussed and the main challenges for the near future presented. Overall, it is concluded that electroactive smart materials play an ever-increasing role in neural tissue regeneration, appearing as potentially valuable biomaterials for regenerative purposes.

Synthesis and biological evaluation of a bioinspired, tissue-adhesive gellan gum-based hydrogel designed for minimally invasive delivery and retention of chondrogenic cells.

A dopamine-modified, bioinspired gellan gum hydrogel (STM-148B) with improved physicochemical and biological characteristics, suitable for minimally invasive cell delivery and retention in the context of cartilage repair, is herein presented. STM-148B's putative game-changing design characteristics include a highly biocompatible, animal-free and chemically defined composition, reproducibility of manufacture and ease of formulation. STM-148B undergoes rapid ionic crossinking by physiologically relevant mono and divalent cations to form stable 3D hydrogels that possess excellent tissue adhesiveness, such that additional fixation aids are rendered superfluous. STM-148B hydrogels maintain viability of mammalian cells and further promote up-regulation of the expression of healthy chondrogenic extracellular matrix markers upon stimulation. STM-148B is currently undergoing pre-clinical safety and efficacy assessment as a medical device for cell delivery and retention focussing on regeneration of hyaline-like cartilage and may represent a valuable addition to the armamentarium of tissue-engineering therapies for treatment of focal cartilage lesions.