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Hydrogel Mediated Delivery of Trophic Factors for Neural Repair Joshua S Advanced Review Hydrogel mediated delivery of trophic factors for neural repair Joshua S. Katz1 and Jason A. Burdick∗ Neurotrophins have been implicated in a variety of diseases and their delivery to sites of disease and injury has therapeutic potential in applications including spinal cord injury, Alzheimer’s disease, and Parkinson’s disease. Biodegradable polymers, and specifically, biodegradable water-swollen hydrogels, may be advantageous as delivery vehicles for neurotrophins because of tissue-like properties, tailorability with respect to degradation and release behavior, and a history of biocompatibility. These materials may be designed to degrade via hydrolytic or enzymatic mechanisms and can be used for the sustained delivery of trophic factors in vivo. Hydrogels investigated to date include purely synthetic to purely natural, depending on the application and intended release profiles. Also, flexibility in material processing has allowed for the investigation of injectable materials, the development of scaffolding and porous conduits, and the use of composites for tailored molecule delivery profiles. It is the objective of this review to describe what has been accomplished in this area thus far and to remark on potential future directions in this field. Ultimately, the goal is to engineer optimal biomaterials to deliver molecules in a controlled and dictated manner that can promote regeneration and healing for numerous neural applications. 2008 John Wiley & Sons, Inc. Wiley Interdiscipl. Rev. Nanomed. Nanobiotechnol. 2009 1 128–139 isruption of central nervous system (CNS) or Neurotrophins have been widely investigated for Dperipheral nervous system (PNS) tissues such their influence on cell mortality, differentiation, and as the spinal cord, optic nerve, and motor neurons function in both the CNS and the PNS.6 These neu- can severely affect a patient’s motor, sensory, rotrophins include factors such as nerve growth factor and autonomic functions, and depending on the (NGF), brain-derived neurotrophic factor (BDNF), severity of the injury, the patient’s quality of life neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), can decline dramatically.1–3 Unfortunately, current and glial derived neurotrophic factor (GDNF). Neu- clinical treatment options are severely limited for rotrophins bind to tropomyosin-related kinase (Trk) many of these injuries and diseases and are unable receptors (TrkA for NGF, TrkB for BDNF and NT- to restore complete function to these patients. For 4/5, and TrkC for NT-3) and the pan-neurotrophin instance, in the spinal cord, one significant barrier receptor p75.7 The functions of neurotrophins in to regeneration is the extremely complex cascade of vivo are many and include controlling neural cell events (e.g., inflammation, glial scarring, release of growth and survival, influencing glial development, inhibitory molecules) that occurs after injury that and functions in non-neural tissues such as in the must be addressed to restore functional recovery to cardiovascular and immune systems.8–12 Addition- the patient.4,5 However, one promising therapy is the ally, neurotrophins can mediate axon signals or act delivery of neurotrophins that can influence the local on myelinating glia to influence the remyelination function of cells within and surrounding the injury site. of axons.13,14 For example, neurotrophins can pro- mote axonal growth, neuronal survival, and plasticity ∗ Correspondence to: Jason A. Burdick, Department of Bioengineer- after injury to the spinal cord.15 Lu and coworkers16 ing, University of Pennsylvania, 240 Skirkanich Hall, 210 S. 33rd Street, Philadelphia, PA 19104, USA. recently illustrated the ability of NT-3 in combination E-mail: [email protected] with cyclic adenosine monophosphate to induce regen- 1Department of Bioengineering, University of Pennsylvania, 240 eration of sensory axons past a spinal cord lesion. Skirkanich Hall, 210 S. 33rd Street, Philadelphia, PA 19104, USA Additionally, the overexpression of neurotrophins DOI: 10.1002/wnan.010 after injury induced sprouting of corticospinal tract 128 2008JohnWiley&Sons,Inc. Volume1,January/February2009 WIREs Nanomedicine and Nanobiotechnology Hydrogel mediated delivery of trophic factors axons past the injury site.17 Techniques such as gene INJECTABLE HYDROGELS therapy, delivery via stem cells, and polymeric delivery Hydrogels are made injectable through numerous vehicles are being investigated for the supplementation means including free-radical polymerizations (i.e., 6 of neurotrophins to injured neural tissues. thermal, photo, or redox initiation), self-assembly There are several methods which have been of materials, or ionic crosslinking.27 One of the explored for the delivery of neurotrophins and drugs biggest advantages to using injectable materials for to the nervous system, including mini-pumps, genet- these applications is the non-invasiveness of hydrogel ically modified cells, and polymer formulations.18–20 delivery, which can limit further tissue damage. For Hydrogels are water-swollen insoluble polymer net- instance, disruption of the dura cover to many tissues works that have a wide range of chemical compo- (including the brain and spinal cord) results in the sitions and properties.21–23 Hydrogels can be formed loss of many potentially stimulatory molecules, which through a variety of mechanisms, including both phys- could be avoided with injection through the dura. ical (e.g., ionic or hydrogen bonding) and chemical Additionally, many imaging techniques could be used in combination with the injection procedures to gelation (e.g., covalent bonding). Through alterations potentially deliver these hydrogels in a closed surgery. in the chemical structure, important properties such as Several clinically used biomaterials are already swelling, degradation (e.g., hydrolytic or enzymatic), injected in vivo, such as poly(methyl methacrylate) and mechanics can be controlled. The delivery of bone cements28,29 and photocurable resins for filling large molecules, such as neurotrophins, is typically dental caries,30 and neural applications could benefit accomplished by encapsulating the molecules during from similar procedures. This section focuses on the gelation, which are subsequently released via diffu- various injectable hydrogels that have been explored sion and degradation mechanisms. This process is for delivery of growth factors for neurological relatively complex and dynamic as the hydrogel mesh applications. size changes as the material degrades and swells. With Agarose is a polysaccharide derived from recent advances in polymer synthesis and our under- seaweed and comprised of repeating galactopyranose standing of biological polymers, our ability to control units. It has been used for a variety of biomedical hydrogels, and consequently, molecule delivery is con- applications and can be thermally induced to form a 24 hydrogel through intermolecular hydrogen bonding stantly improving. 31,32 There are numerous factors that make hydrogels interactions. At elevated temperatures when hydrogen bonds cannot form, agarose solutions do ideal delivery vehicles for neurotrophic factors and not gel. However, as the solution is cooled, hydrogen repair of neural tissue. First, this approach does not bonds begin to form, leading to gelation. Jain and introduce either live tissue (e.g., grafts) or viral vectors, coworkers33 used cooled nitrogen gas to gel solutions eliminating potential issues with graft rejection and of agarose in situ. Following injury to the spinal adverse responses. Next, hydrogel delivery eliminates cord, a solution of agarose containing BDNF-loaded the need for devices like pumps and catheters that can microtubules was pipetted into the injury site. The malfunction. Finally, hydrogels can provide constant solution was then cooled by nitrogen gas which and tailorable delivery of either one or numerous was passed over a bath of dry ice to produce a molecules to a desired in vivo location. Because of gel. A schematic of this cooling system is shown in the short in vivo half life of neurotrophins, sustained Figure 1(a). The presence of BDNF greatly enhanced delivery to the injury site results in significantly better the regeneration of axons and their ability to penetrate recovery compared to a single injection.25,26 Because into and through the scaffold. of the complexity of injuries, the appropriate delivery Another natural polymer, collagen, crosslinks profile depends on the injured tissue and timing of at physiological conditions through ionic interac- tions with salts present in solution. Hamann and therapies. Several hydrogels have been investigated coworkers35,36 injected aqueous solutions of collagen for the controlled delivery of neurotrophins and containing growth factors (epidermal growth factor it is the objective of this review to outline past (EGF) and/or FGF-1) into the intrathecal space sur- work in this area and look forward to future rounding the spinal cord as a drug delivery system. directions. The hydrogels investigated have ranged in Rather than acting as a mechanical support for axonal composition from purely synthetic (e.g., poly (ethylene regeneration as seen in many other systems, this sys- glycol) (PEG)) to purely natural (e.g., collagen), and tem chemically supports the regenerative response to in physical structure from uniform gels to porous spinal cord injury (SCI) by the delivery of therapeu- scaffolds and composite materials. tic agents directly and locally to the site of injury.
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