Hydrogels, due to their unique biocompatibility, flexible methods of synthesis, range of constituents, and desirable physical characteristics, have been the material of choice for many applications in regenerative medicine. They can serve as scaffolds that provide structural integrity to tissue constructs, control drug and protein delivery to tissues and cultures, and serve as adhesives or barriers between tissue and material surfaces. In this work, the properties of hydrogels that are important for tissue engineering applications and the inherent material design constraints and challenges are discussed. Recent research involving several different hydrogels polymerized from a variety of synthetic and natural monomers using typical and novel synthetic methods are highlighted. Finally, special attention is given to the microfabrication techniques that are currently resulting in important advances in the field.

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Hydrogels in regenerative medicine

Degeneration and regeneration of the nervous system

Most organs and biological tissues are soft viscoelastic materials with elastic moduli ranging from on the order of 100 Pa for the brain to 100 000 Pa for soft cartilage. Biocompatible synthetic materials already have many applications, but combining chemical compatibility with physiologically appropriate mechanical properties will increase their potential for use both as implants and as substrates for tissue engineering. Understanding and controlling mechanical properties, specifically softness, is important for appropriate physiological function in numerous contexts. The mechanical properties of the substrate on which, or within which, cells are placed can have as large an impact as chemical stimuli on cell morphology, differentiation, motility, and commitment to live or die.

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Soft biological materials and their impact on cell function

Designing of biologically active scaffolds with optimal characteristics is one of the key factors for successful tissue engineering. Recently, hydrogels have received a considerable interest as leading candidates for engineered tissue scaffolds due to their unique compositional and structural similarities to the natural extracellular matrix, in addition to their desirable framework for cellular proliferation and survival. More recently, the ability to control the shape, porosity, surface morphology, and size of hydrogel scaffolds has created new opportunities to overcome various challenges in tissue engineering such as vascularization, tissue architecture and simultaneous seeding of multiple cells. This review provides an overview of the different types of hydrogels, the approaches that can be used to fabricate hydrogel matrices with specific features and the recent applications of hydrogels in tissue engineering. Special attention was given to the various design considerations for an efficient hydrogel scaffold in tissue engineering. Also, the challenges associated with the use of hydrogel scaffolds were described.

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Hydrogel scaffolds for tissue engineering: Progress and challenges

Several nerve guidance conduits (NGCs) and nerve protectant wraps are approved by the US Food and Drug Administration (FDA) for clinical use in peripheral nerve repair. These devices cover a wide range of natural and synthetic materials, which may or may not be resorbable. This review consolidates the data pertaining to all FDA approved materials into a single reference, which emphasizes material composition alongside pre-clinical and clinical safety and efficacy (where possible). This article also summarizes the key advantages and limitations for each material as noted in the literature (with respect to the indication considered). In this context, this review provides a comprehensive reference for clinicians which may facilitate optimal material/device selection for peripheral nerve repair. For materials scientists, this review highlights predicate devices and evaluation methodologies, offering an insight into current deficiencies associated with state-of-the-art materials and may help direct new technology developments and evaluation methodologies thereof.

FDA approved guidance conduits and wraps for peripheral nerve injury: A review of materials and efficacy

Biological nerve grafts have been extensively utilized in the past to repair peripheral nerve injuries. More recently, the use of synthetic guidance tubes in repairing these injuries has gained in popularity. This review focuses on artificial conduits, nerve regeneration through them, and an account of various synthetic materials that comprise these tubes in experimental animal and clinical trials. It also lists and describes several biomaterial considerations one should regard when designing, developing, and manufacturing potential guidance channel candidates. In the future, it it likely that the most successful synthetic nerve conduit will be one that has been fabricated with some of these strategies in mind.

Peripheral nerve regeneration through guidance tubes.

Purpose: As alternatives to nerve grafts for peripheral nerve repair, we have synthesized 12 mm long poly(2- hydroxyethyl methacrylate-co-methyl methacrylate) (PHEMA-MMA) porous tubes and studied their regenerative capacity for the repair of surgically-created 10 mm rat sciatic nerve gaps. We compared the in vivo regenerative efficacy of these artificial tubes with the gold standard, the nerve autograft. Methods: Tubes were assessed in vivo for their ability to support nerve regeneration at 4, 8, and 16 weeks post-implantation by histology, electrophysiology, histomorphometry, and reinnervated lateral gastrocnemius (LG) dry muscle mass. Results: Axonal regeneration within the tubes was observed by 8 weeks, with outcome parameters comparable to autografts. This finding was further supported by the electrophysiological and histomorphometric results. The 16 week tube group had a bimodal response, with 60% of the tubes having a similar response to autografts and the other 40% having significantly lower ( p< 0.05) outcome measures in several parameters. Conclusions: Axonal regeneration in artificial tubes was similar to that in autografts at 8 and 16 weeks, however, a bimodal distribution of regeneration was observed in 16 week tubes.

Peripheral nerve regeneration through a synthetic hydrogel nerve tube

Long-term in vivo biomechanical properties and biocompatibility of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) nerve conduits.

Coil-reinforced hydrogel tubes promote nerve regeneration equivalent to that of nerve autografts.

OBJECTIVE: To investigate whether or not it is the frustrated growth state (no axon growth) that reduces regenerative capacity or the inability of axotomized motoneurons to remake muscle connections (axon growth-no muscle contact) that accounts for poor regenerative capacity of chronically axotomized motoneurons. METHODS: We chronically axotomized rat femoral motoneurons for 2 months by cutting the nerve and either capping the proximal nerve to prevent axon regeneration (Group 1, no axon growth for 2 mo) or encouraging axon regeneration but not target reinnervation by suture to the distal stump of cut saphenous nerve (Group 2, axon growth with no muscle contact). In the control fresh axotomy group (axon growth with muscle contact), femoral nerve stumps were resutured immediately. Two months later, the femoral nerve was recut and sutured immediately to encourage regeneration in a freshly cut saphenous nerve stump for 6 weeks. Regenerating axons in the saphenous nerve were back-labeled with fluorogold for enumeration of the femoral motoneurons that regenerated their axons into the distal nerve stump. RESULTS: We found that significantly fewer chronically axotomized motoneurons regenerated their axons than freshly axotomized motoneurons that regenerated their axons to reform nerve-muscle connections in the same length of time. The number of motoneurons that regenerated their axons was reduced in both the conditions of no axon growth and axon growth with no muscle contact; thus chronic axotomy for a 2-month period reduced regenerative success irrespective of whether the motoneurons were prevented from regenerating or encouraged to regenerate their axons in that same period of time. CONCLUSION: Axonal regeneration does not protect motoneurons from the negative effects of prolonged axotomy on regenerative capacity. It is the period of chronic axotomy, in which motoneurons remain without target nerve-muscle connection, and not simply a state of frustrated growth that accounts for the reduced regenerative capacity of those neurons.

Jason S. Belkas

Papers

Peripheral nerve regeneration through guidance tubes.

Peripheral nerve regeneration through a synthetic hydrogel nerve tube

Long-term in vivo biomechanical properties and biocompatibility of poly(2-hydroxyethyl methacrylate-co-methyl methacrylate) nerve conduits.

Coil-reinforced hydrogel tubes promote nerve regeneration equivalent to that of nerve autografts.

Prolonged target deprivation reduces the capacity of injured motoneurons to regenerate.