A Review of Bioactive Release from Nerve Conduits as a Neurotherapeutic Strategy for Neuronal Growth in Peripheral Nerve Injury

Abstract

Peripheral nerve regeneration strategies employ the use of polymeric engineered nerve conduits encompassed with components of a delivery system. This allows for the controlled and sustained release of neurotrophic growth factors for the enhancement of the innate regenerative capacity of the injured nerves. This review article focuses on the delivery of neurotrophic factors (NTFs) and the importance of the parameters that control release kinetics in the delivery of optimal quantities of NTFs for improved therapeutic effect and prevention of dose dumping. Studies utilizing various controlled-release strategies, in attempt to obtain ideal release kinetics, have been reviewed in this paper. Release strategies discussed include affinity-based models, crosslinking techniques, and layer-by-layer technologies. Currently available synthetic hollow nerve conduits, an alternative to the nerve autografts, have proven to be successful in the bridging and regeneration of primarily the short transected nerve gaps in several patient cases. However, current research emphasizes on the development of more advanced nerve conduits able to simulate the effectiveness of the autograft which includes, in particular, the ability to deliver growth factors.

Scaffolds for Peripheral Nerve Regeneration, the Importance of In Vitro and In Vivo Studies for the Development of Cell-Based Therapies and Biomaterials: State of the Art

“…In fact, single exogenous dosage of BDNF has shown better results than continuous long-term applications [258]. It is reported that muscle regeneration causes the overexpression of GDNF which increases the number of motor axons in the neuromuscular junctions in vivo [259][260][261][262][263][264][265][266]. Also, GDNF is a potent protective factor against axotomy-induced motor and sensory neuron death [267][268][269][270].…”

Time‐restricted release of multiple neurotrophic factors promotes axonal regeneration and functional recovery after peripheral nerve injury

“…This is consistent with the growing appreciation that application of multiple NTFs, rather than a single type, holds greater therapeutic promise. Noncellular delivery strategies could deliver multiple NTFs, but undesired initial burst release and loss of bioactivity as time progresses hamper the therapeutic effect (8,18,(25)(26)(27)(28). Cellular delivery systems show advantages to providing bioactive NTFs with adequate doses and release kinetics at the site of action and avoiding toxic effects of nonphysiologic protein degradation or aggregation products (28).…”

“…In addition, the release kinetics of NTFs are also an important factor that affects repair outcomes. The burst release of a too-high dose of NGF may hinder axonal growth because of the down-regulation of tropomyosin receptor kinase A and loss of affinity of tropomyosin receptor kinase A to the growth factors (15)(16)(17)(18). Furthermore, many studies have found that a microenvironment with prolonged, high levels of NTFs, which last for several months or even years, is not necessary for nerve regeneration (19,20) and even has an adverse effect on functional recovery and on the elongation of the axon toward the distal target (7).…”

“…To achieve this goal, various NTF delivery strategies have been developed. Noncellular delivery strategies, including polymer-, affinity-, and instrument-based delivery systems, hold the potential to incorporate single and multiple NTFs, but undesired initial burst release and loss of bioactivity with time hamper their therapeutic effects (8,10,18,(25)(26)(27). Cellular delivery systems, including nonviral and viral vector-mediated NTF expression, can provide bioactive NTFs in adequate doses and with release kinetics at the site of action and can avoid toxic effects of nonphysiologic protein degradation or aggregation products (28).…”

Advances in the neurological and neurosurgical management of peripheral nerve trauma

“…Dosing and drug kinetics play an important role in the efficacy of growth factor strategies and excessive delivery can actually impede axonal regeneration 66. A number of biotechnology strategies are being used to develop optimum delivery methods,67 but presently none are approved for use in clinical practice.…”