Biomedical Engineering Reference
In-Depth Information
Toxicity Testing
P4HB and P3HB-4HB have been evaluated in preclinical tests recommended
by the FDA for medical devices. These tests include cytotoxicity, sensitization,
irritation and intracutaneous reactivity, hemocompatibility, and implanta-
tion. Thus for example, P4HB films and sutures were subjected to a complete
series of biocompatibility test protocols that were performed in accordance
with the FDA's GLP regulations as set forth in 21 CFR, part 58, as well as ISO
10993-1. The test results confirmed that P4HB is nontoxic and biocompatible
(Martin DP, personal communication).
The degradation product 4HB is a natural metabolite present in the hu-
man brain, heart, lung, liver, kidney, and muscle [248]. It has recently been
approved by the FDA for treatment of cataplexy [249]. In higher doses,
4HB possesses psychopharmaceutical effects leading to abuse as “liquid ec-
stasy” [250]. However, the low amount of monomer released during the poly-
mer degradation together with the short in vivo half-life of 4HB makes it
highly unlikely that small P4HB implants, such as those used in cardiovascu-
lar tissue engineering, will cause pharmacological side-effects [47].
Cell Culture Studies
In vitro cytotoxicity studies using L929 mouse fibroblasts revealed compara-
ble cell compatibility of P3HB, P4HB, and P3HB-18%4HB films [51]. Other
cell types have been successfully seeded on P4HB and tested in tissue en-
gineering experiments, mostly for cardiovascular applications. For example,
porous P4HB matrices have been seeded with ovine vascular cells, and cell
attachment and growth was compared to that on PGA or P3HO-3HH ma-
trices. Although cell attachment on P4HB was low, it was considered to
be sufficient for the application as heart valve scaffold [44]. Porous P4HB
scaffolds seeded with ovine vascular cells have also been tested as a car-
diovascular patch [42] or vascular graft [46, 251]. PGA matrices coated by
a P4HB film layer have been successfully seeded with different types of
cells, such as ovine vascular myofibroblasts and endothelial cells [43, 45, 252,
253], endothelial progenitor cells [254], marrow stromal cells [255-257], hu-
man pediatric aortic cells [258], human umbilical cord cells [259], human
mesenchymal placental cells [260], or ovine skeletal myoblasts [261] (see
Sect. 4.4).
In Vivo Studies
Mild tissue reactions have been observed in several in vivo studies. For ex-
ample, a minimal foreign body reaction has been reported after s.c. implan-
tation of P4HB in rats [56]. The analysis of patches tested to augment the
pulmonary artery in sheep revealed a little remaining polymer 24 weeks post-
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