Table 1.
Evidence extracted from animal studies selected.
| Authors and Year of Publication | Nerve (Type)/Gap Size/Time Periods | Animal (n) | PHB Formula Used | Scaffold Fabrication Method | Additive (If Any) |
Methods Used | Conclusion or Main Outcome |
|---|---|---|---|---|---|---|---|
| Borkenhagen et al., 1998 [13] | Sciatic nerve (mixed)/8 mm/4, 12, 24 weeks | Rats (26) | Poly[glycolide-co-(ε-caprolactone)]-diol & poly[(R)-3-hydroxybutyric acid-co-(R)-3-hydroxyvaleric acid]-diol (all polymers had a molecular weight higher than 100 KDa) |
Melt extrusion (tube) | No additive | Macroscopic morphology, histology | PHB holds promises for its utilization as nerve guidance channels. |
| Ljungberg et al., 1999 [14] | Superficial radial nerve (sensory)/~2–3 mm/6, 12 months | Cats (20) | Polyhydroxybutyrate (PHB) (molecular weight 150 KDa) |
Rolled sheets (tube) and fibrin glue. | No additive | Histology, quantitative immunohistochem. (IHC) | No differences between wrapping the nerve ends in PHB sheet or epineurally suturing of the nerve. |
| Hazari et al., 1999a [15] | Radial Nerve (mixed)/2–3 mm/6, 12 months | Cats (20) | Poly-3-hydroxbutyrate (PHB) (molecular weight 150 KDa) |
Rolled PHB sheet wrapped around the nerve ends & Tissue Glue | No additive | Histology, quantitative IHC | No differences beetwen PHB tube and Epineural Repair |
| Hazari et al., 1999b [16] | Sciatic nerve (mixed)/10 mm/7, 14, 30 days | Rats (36) | Poly-3-hydroxybutyrate (molecular weight 150 KDa) |
Rolled sheets sealed longitudinallywith cyanoacrylate (tube) | No additive | Quantitative IHC, morphometry | Good nerve regeneration in comparison with nerve grafts. |
| Young et al., 2002 [17] | Common peroneal nerve (Mixed)/2, 3, 4 cm/2, 3, 6, 9 weeks | Rabbit (90) | Poly-3-hydroxybutyrate (PHB) (molecular weight 150 KDa) |
Sterile PHB sheets with unidirectional fiber orientation (long axes) | No additive | IHC, histology, macroscopic morphology | PHB conduits support peripheral nerve regeneration up to 63 days. They are suitable for long-gap nerve injury repair. |
| Mohanna et al., 2003 [18] | Common peroneal nerve (Mixed)/2, 4 cm/3, 6, 9 weeks | Rabbit (90) | Poly 3-hydroxybutyrate (PHB) (molecular weight 150 KDa) |
Rolled PHB sheet around (16 G) cannula, long axes fiber orientation | Glial growth factor (rhGGF2, 1.29 mg mL−1, 80 kDa) diluted in 1 mL of 50:50 alginate fibronectin solution | Quantitative IHC | Inhibition of regeneration of nerve regeneration was partially reversed by the addition of GGF to the PHB conduits. PHB-GGF stimulates a progressive and sustainable regeneration increase in long nerve gap conduits. |
| Hart et al., 2003 [19] | Sciatic nerve (mixed)/10 mm/2, 4 months | Rats (30) | Poly-3-hydroxybutyrate (PHB) (molecular weight 150 KDa) |
Rolled sheets (tube) PHB sheets—compressed PHB fibers (2–20 µm Ø) |
Leukemia inhibitory factor (recombinant murine rhLIF 100 ng/mL) hosted in a matrix of hydrogel comprising 2% ultra-pure low-molecular-weight high-mannuronic-acid-content calcium alginate and 0.05% bovine fibronectin | Quantitative IHC, macro morphometry | rhLIF has a potential role in promoting peripheral nerve regeneration after secondary repair and can be effectively delivered within PHB conduits for nerve repair. |
| Birchall et al., 2004 [20] | Recurrent laryngeal nerve (mixed)/4 mm/30, 60, 120 days | Minipig (6) | Polyhydroxybutyrate (PHB) (molecular weight 150 KDa) |
PHB sheet rolled to form a conduit | No additive | IHC; morphometry; histologic quantif.; macroscopic morphology | Functional and histological recovery within 2–4 months and appears to sustain abductor muscle fiber morphology. Recovery occurs despite a complex inflammatory response. |
| Mohanna et al., 2005 [21] | Peroneal (mixed)/20, 40 mm/120 days | Rabbit (30) | Poly-3-hydroxybutyrate (PHB) (molecular weight 150 KDa) |
Rolled sheets (tube) PHB sheets—compressed PHB fibers (2–20 µm Ø) |
Glial growth factor (rthGGF2, 1.29 mg mL−1, 80 kDa) diluted in 1 mL of 50:50 alginate fibronectin solution | Histology, quant. IHC, ultrastructure (TEM), muscle atrophy | GGF-containing PHB conduits promoted sustained axonal regeneration and improved target muscle reinnervation. |
| Kalbermatten et al., 2008a [22] | Sciatic (mixed)/10 mm/2 weeks | Rats (24) | Poly-3-hydroxybutyrate (PHB) (molecular weight 150 KDa) |
PHB sheets rolled (16 G) 14 mm long, 2 mm diameter | A fibrinogen-cell solution was made in 1:10 dilution from Tisseel® containing 9 mg/mL fibrinogen and 80 × 106 Schwann cells/mL. This solution (25 mL) was used to coat PHB that was treated with 25 mL of diluted thrombin solution (5 IU/mL) for 10 min. | Histology, IHC, macroscopic morphology | Beneficial combinatory effect of an optimized matrix, cells and conduit material (PHB) as a step towards bridging nerve gaps. |
| Kalbermatten et al., 2008b [23] | Sciatic (mixed)/10 mm/2 weeks | Rats (12) |
Poly-3-hydroxybutyrate (PHB) (molecular weight 150 KDa) |
Rolled sheets of compressed PHB fibers soaked in fibrin glue (tube) | About 80 × 106 Schwann cells/mL were suspended in 25 mL of fibrinogen solution. PHB conduits were coated with 25 mL of a diluted thrombin (5 IU/mL) solution for 10 min and then the fibrinogen/cell solution was added. | Histology, IHC, macroscopic morphology | PHB showed significant advantage in rapidly connecting a nerve gap lesion. |
| Kalbermatten et al., 2008c [24] | Sciatic (mixed)/10 mm/2, 4 weeks | Rodents (12) |
Poly-3-hydroxybutyrate (PHB) (molecular weight 150 KDa) |
PHB sheets wrapped around a cannula and heat sealed (tube) vs. Fibrin conduits. | No additive | Quantitative IHC, morphology | Advantage of the new fibrin conduit for the important initial phase of peripheral nerve regeneration in comparison with PHB conduit. |
| Bian et al., 2009 [25] | Sciatic (mixed)/10 mm/1, 2, 3 months | Rats (60) | Poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx) (molecular weight 610 KDa) |
Dipping–leaching | No additive | Electrophysiol. analysis, histology, ultrastructure (TEM) | PHBHHx nerve conduits showed proper mechanical strengths and biodegradability artificial nerve conduits to repair nerve damages. |
| Durgam et al., 2010 [27] | Sciatic (mixed)/10 mm/8 weeks | Rats (11) | Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB-HV) (no information on molecular weight) |
Rolled sheets of PCL and PECA glued with a PHB-HV solution (tube) | Co-polymers of polypyrrole (PPy) with poly (ε-caprolactone) (PCL) and poly (ethyl cyanoacrylate) (PECA). Melt-pressed PHB-HV films were airbrushed with a PPy co-polymer (PPy–PCL or PPy–PECA) and pressed. | Histology | Biomaterials (PCL, PECA and PHB-HV) have good biocompatibility and support proliferation and growth neurons in vivo (without electrical stimulation). |
| Schaakxs et al., 2017 [33] | Sciatic (mixed)/10 mm/12 weeks | Rats (15) | Poly-3-hydroxybutyrate (PHB) (molecular weight 150 KDa) |
Rolled sheets of compressed PHB fibers soaked in fibrin glue (tube) | Primary Schwann cells (SCs) isolated from adult rat sciatic nerves or SC-like differentiated adipose-derived stem cells (dASCs) from rats were trypsinised and 80 × 106 cells/mL were suspended in 25 μL diluted fibrinogen solution. The PHB strips were coated with 25 μL diluted thrombin (5 IU/mL) solution for 10 min and then the cell solution was added. | Functional gait test EMG, morphometry | The PHB strip seeded with cells provides a beneficial environment for nerve regeneration. |
| Ozer et al., 2018 [34] | Sciatic (mixed)/10 mm/8 weeks | Rats (30) | Poly-3-hydroxybutyrate (PHB) (molecular weight 454 kDa) |
PHB (5 wt%) in chloroform by electrospinning method | Chitosan-coated PHB conduits were seeded with mesenchymal stem cells harvested from human iliac bone marrow (hMSC-bm) | Functional gait test, EMG, histology | PHB/chitosan-hMSC-bm nerve conduits may be a useful artificial guide for nerve regeneration. |