In vivo degradation of porous poly(propylene fumarate)/poly(DL-lactic-co-glycolic acid) composite scaffolds

Chemical messengers such as neurotransmitters play an important role in cell communication, differentiation, and survival. We have designed and synthesized a bioactive biomaterial that derived its biological activity from dopamine. The resultant biodegradable polymer, PCD, has pendent groups bearing dopamine functionalities. Image analysis demonstrated that nerve growth factorprimed rat pheochromocytoma cells (PC12) and explanted rat dorsal root ganglions attached well and displayed substantial neurite outgrowth on the polymer surface. Furthermore, PCD promoted more vigorous neurite outgrowth in PC12 cells than tissue culture polystyrene, laminin, and poly(D-lysine). The histogram of neurite length of PC12 cells showed distinctive patterns on PCD that were absent on the controls. A subset of PC12 cells displayed high filopodium density on PCD. The addition of dopamine in culture medium had little effect on the differentiation of PC12 cells on tissue culture polystyrene. Tyrosine, the precursor of dopamine, did not exhibit this ability to impart specific bioactivity to an analogous polymer. Thus, the dopamine functional group is likely the origin of the inductive effect. PCD did not cause nerve degeneration or fibrous encapsulation when implanted immediately adjacent to the rat sciatic nerves. This work is a step toward creating a diverse family of bioactive materials using small chemical messengers as monomers.neurotransmitter ͉ regenerative medicine B iomaterials are widely used in disease treatment and improving human well-being (1, 2). Recently, significant advances have been made to impart biological activity to biomaterials. Most of the existing bioactive materials are derived from extracellular matrix or are modified with extracellular matrix motifs (3-8). The most widely used extracellular matrix motifs include protein epitopes such as Arg-Gly-Asp (4, 5, 9), Tyr-IleGly-Ser-Arg (10, 11), and Ile-Lys-Val-Ala-Val (6, 11) and glycosaminoglycans such as heparin (12,13). In addition to cellextracellular matrix interactions, cell differentiation and survival also depend on constant interactions with other cells through a plethora of messenger molecules (14-16). The biomaterial reported here is designed to use a chemical messenger to impart bioactivities to the resultant biodegradable polymers.We chose to focus on using bioactive materials for functional restoration of damaged nerves because it is a major challenge in medicine (17). An important class of chemical messengers in the nervous system is the neurotransmitters (18, 19). They are essential to neuronal outgrowth during embryonic and neonatal development and after injury (20-23). The depletion of neurotransmitters during embryonic development results in developmental defects of the brain, suggesting that neurotransmitters play crucial roles as morphogens or neurotrophic factors (24). Dopamine in particular is vital in axon growth and synapse formation during the embryonic stage (25). We postulated that a biocompatible material containing dopamine functiona...

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“…The ester bond in PCD rendered the polymer biodegradable, with a half-life in PBS solution (29,30) of Ϸ50 days at 37°C (Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

A neuroinductive biomaterial based on dopamine

Gao

Kim

Coe

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition to the defect size, the in vivo model selected should mimic the clinical situation as closely as possible 3,4 and provide a challenging environment that will allow the investigators to discriminate the healing potential of various biomaterials and tissue-engineering constructs. 5 Although both cranial cavitational defect [6][7][8][9] and long bone segmental defect [10][11][12] models are commonly performed in small rodents to test bone regeneration materials, they cannot address the unique masticatory stresses and cell populations seen in the wound healing environment of alveolar bone defects. 13,14 Previous studies have created 4-mm defects in the rat mandible, which fail to heal at 24 weeks.…”

Section: Introductionmentioning

confidence: 99%

Development and characterization of a rabbit alveolar bone nonhealing defect model

Young

Bashoura

Borden

et al. 2007

J Biomedical Materials Res

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The aim of this study was to develop an easily accessible and reproducible, nonhealing alveolar bone defect in the rabbit mandible. Twenty-four adult male New Zealand white rabbits underwent unilateral mandibular defect surgery. Two types of defect in the premolar/molar region were compared: (1) a 10-mm "full thickness" cylindrical defect removing both cortical plates and the intervening trabecular bone and tooth roots; (2) a 10-mm "partial thickness" cylindrical defect removing only the lateral bony cortex, trabecular bone, and tooth roots. Both types of defect were examined at 0, 8, and 16 weeks using histology and/or microcomputed tomography to determine the quality and quantity of bone formation. The partial thickness defect displayed significant bone fill at 8 weeks (86.9% +/- 10.8%), and complete regeneration of bony contours and bridging by 16 weeks. In contrast, the full thickness defect was never able to bridge itself and displayed no significant difference in bone regeneration between the 8-week (61.5% +/- 3.7%) and 16-week (55.1% +/- 18.5%) time points. These results indicate that a nonhealing defect can be created with a 10-mm bicortical cylindrical ostectomy placed in the premolar/molar region of the rabbit mandible, demonstrating the potential of this animal model as a test bed for mandibular biomaterials and tissue-engineering constructs.

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“…[6][7][8] While some studies did observe an increased inflammatory response and osteoclastic activity, only the full impact of these events on tissue formation may be determined by monitoring complete scaffold degradation. Since bone resorption was observed adjacent to PLAGA absorbable screws at 4 months [9] and PLAGA constructs used in segmental bone defects are likely to contain a greater volume of polymer, long-term polymeric degradation studies are imperative.…”

Section: Introductionmentioning

confidence: 99%

The Implications of Polymer Selection in Regenerative Medicine: A Comparison of Amorphous and Semi‐Crystalline Polymer for Tissue Regeneration

Kofron

Griswold

Kumbar

et al. 2009

Adv Funct Materials

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Biodegradable polymeric scaffolds are being investigated as scaffolding materials for use in regenerative medicine. While the in vivo evaluation of various three‐dimensional (3D), porous, biodegradable polymeric scaffolds has been reported, most studies are ≤3 months in duration, which is typically prior to bulk polymer degradation, a critical event that may initiate an inflammatory response and inhibit tissue formation. Here, a 6 month in vitro degradation and corresponding in vivo studies that characterized scaffold changes during complete degradation of an amorphous, 3D poly(lactide‐co‐glycolide)(3D‐PLAGA) scaffold and near‐complete degradation of a semi‐crystalline3D‐PLAGA scaffold are reported. Using sintered microsphere matrix technology, constructs were fabricated in a tubular shape, with the longitudinal axis void and a median pore size that mimicked the architecture of native bone. Long‐term quantitative measurements of molecular weight, mechanical properties, and porosity provided a basis for theorization of the scaffold degradation process. Following implantation in a critical size ulnar defect model, histological analysis and quantitative microCT indicated early solubilization of the semi‐crystalline polymer created an acidic microenvironment that inhibited mineralized tissue formation. Thus, the use of amorphous over semi‐crystalline PLAGA materials is advocated for applications in regenerative medicine.

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In vivo degradation of porous poly(propylene fumarate)/poly(DL-lactic-co-glycolic acid) composite scaffolds

Cited by 101 publications

References 25 publications

A neuroinductive biomaterial based on dopamine

A neuroinductive biomaterial based on dopamine

Development and characterization of a rabbit alveolar bone nonhealing defect model

The Implications of Polymer Selection in Regenerative Medicine: A Comparison of Amorphous and Semi‐Crystalline Polymer for Tissue Regeneration

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