**5. Allografts**

Conceptually, a good alternative to autographs is cellular cadaveric allografts. First, they would avoid the need to sacrifice a sensory nerve function; second, they provide both a three-dimensional extracellular matrix for supporting and promoting axon regeneration and Schwann cells, which can release neurotrophic factors for promoting axon regeneration. However, using allografts requires the administration of immunosuppressive drugs to avoid graft rejection and regeneration failure [123], but immunosuppressants are associated with significant clinical morbidity [124]. They also cause unwanted side e ffects, such as suppressing the regeneration-promoting capacity of host Schwann cells [30]. Thus, the use of cellular allografts for peripheral nerve repair is rare and their uses are limited to the most severe cases of nerve injuries, such as those involving repairing long nerve gaps [125].

An alternative to cellular allografts is to use acellular allografts. These can be used without immunosuppression after eliminating their immunogenicity [126]. Although they lack cells, they typically maintain a highly organized extracellular matrix scaffold, which can induce axon regeneration. Acellular nerve allografts, also called processed nerve allografts, are now increasingly used instead of autografts [124,127–131].

In a comparative study bridging 1.4-cm sciatic nerve gaps in rats, acellular allografts, isografts, and empty collagen conduits were seen to induce similar axon regeneration entirely across the gap [126]. Another recent comparative clinical study looked at the success of sensory recovery when digital nerve gaps of 1.4 and 1.8 cm were bridged by acellular nerve grafts and empty collagen tubes. Allografts vs. collagen tubes induced excellent outcomes in 39% vs. 48%, good in 55% vs. 26%, and poor in 6% vs. 26%, respectively [126]. However, for 2.8-cm gaps, isografts were more effective than allografts, but conduits were not effective [120]. Other studies determined that acellular allografts are excellent for promoting axon regeneration across gaps 1–1.5 cm [31], 2–3 cm [131], and up to 5 cm meaningful recovery across gaps [132]. However, similar to autografts, their efficacy decreases with increasing gap length [53] and they are not recommended for (or FDA-approved) use across "long" nerve gaps, considered to be >3 cm in length [55,68,82,125,133–135].

#### *Enhancing the Regeneration-Promoting Capacity of Allografts*

The efficacy of acellular allografts in promoting axon regeneration and functional recovery can be increased by infusing them with neurotrophic factors, such as glial-derived neurotrophic factor (GDNF) [136], nerve growth factor (NGF) [24], BDNF plus ciliary neurotrophic factor (CNTF) [137], VEGF [138], and βNGF and VEGF [139].

Additional techniques for enhancing axons regeneration through long allografts grafts include filling them with platelet-rich plasma (PRP) [140], autologous Schwann cells [141,142], adipose-derived mesenchymal stem cells (ADSCs), or primary Schwann cell-like differentiated bone marrow-derived mesenchymal stem cells (DMSCs) [142–145]. These cells induce enhanced axon regeneration by releasing neurotrophic factors [146,147].

Although acellular allografts and autografts induce similar extents of axon regeneration across short nerve gaps, acellular allografts are less effective when used for long nerve gaps [148]. However, when the efficacy of acellular allografts is enhanced, they induce axon regeneration that is comparable to that induced by autografts. Unfortunately, the techniques required to enhance the efficacy of acellular allografts have only been tested in animal models, and none can presently be applied clinically. Therefore, sensory nerve grafts remain the "gold standard" for bridging long nerve gaps.
