Scaffold Translation: Barriers Between Concept and Clinic

Translation of scaffold-based bone tissue engineering (BTE) therapies to clinical use remains, bluntly, a failure. This dearth of translated tissue engineering therapies (including scaffolds) remains despite 25 years of research, research funding totaling hundreds of millions of dollars, over 12,000 papers on BTE and over 2000 papers on BTE scaffolds alone in the past 10 years (PubMed search). Enabling scaffold translation requires first an understanding of the challenges, and second, addressing the complete range of these challenges. There are the obvious technical challenges of designing, manufacturing, and functionalizing scaffolds to fill the Form, Fixation, Function, and Formation needs of bone defect repair. However, these technical solutions should be targeted to specific clinical indications (e.g., mandibular defects, spine fusion, long bone defects, etc.). Further, technical solutions should also address business challenges, including the need to obtain regulatory approval, meet specific market needs, and obtain private investment to develop products, again for specific clinical indications. Finally, these business and technical challenges present a much different model than the typical research paradigm, presenting the field with philosophical challenges in terms of publishing and funding priorities that should be addressed as well. In this article, we review in detail the technical, business, and philosophical barriers of translating scaffolds from Concept to Clinic. We argue that envisioning and engineering scaffolds as modular systems with a sliding scale of complexity offers the best path to addressing these translational challenges.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90495/1/ten-2Eteb-2E2011-2E0251.pd

The effect of current used bone substitution materials and platelet-rich plasma on periosteal cells by ectopic site implantation: An in-vivo pilot study

The aim of this study was to investigate de novo bone formation following ectopic site implantation of bone substitutes covered by periosteum, with and without the application of autologous platelet-rich plasma (PRP). Twenty-four weeks after subcutaneous implantation of various bone substitutes (bovine hydroxyapatite (bHAP), phycogenic hydroxyapatite (pHAP), and bioglass (BG)) in 35 mini-pigs, bone regeneration rates were compared microradiographically and histologically. Without PRP, bHAP showed a mean de novo bone formation of 32.41%±29.99, in contrast to the other substitute materials where no mineralization could be detected. In combination with PRP, in the bHAP (63.61%±12.98; p±0.03) and pHAP (34.37±29.38; p=0.015) group, significantly higher de novo bone formation was ascertained than without PRP. No ossification could be detected in the BG group. In conclusion, bHAP and pHAP bone substitutes in combination with PRP showed a significant positive effect on periosteal cells by de novo bone formation after ectopic, subcutaneous, low-vascular site implantation

In-vitro evaluation of Polylactic acid (PLA) manufactured by fused deposition modeling

Abstract Background With additive manufacturing (AM) individual and biocompatible implants can be generated by using suitable materials. The aim of this study was to investigate the biological effects of polylactic acid (PLA) manufactured by Fused Deposition Modeling (FDM) on osteoblasts in vitro according to European Norm / International Organization for Standardization 10,993–5. Method Human osteoblasts (hFOB 1.19) were seeded onto PLA samples produced by FDM and investigated for cell viability by fluorescence staining after 24 h. Cell proliferation was measured after 1, 3, 7 and 10 days by cell-counting and cell morphology was evaluated by scanning electron microscopy. For control, we used titanium samples and polystyrene (PS). Results Cell viability showed higher viability on PLA (95,3% ± 2.1%) than in control (91,7% ±2,7%). Cell proliferation was highest in the control group (polystyrene) and higher on PLA samples compared to the titanium samples. Scanning electron microscopy revealed homogenous covering of sample surface with regularly spread cells on PLA as well as on titanium. Conclusion The manufacturing of PLA discs from polylactic acid using FDM was successful. The in vitro investigation with human fetal osteoblasts showed no cytotoxic effects. Furthermore, FDM does not seem to alter biocompatibility of PLA. Nonetheless osteoblasts showed reduced growth on PLA compared to the polystyrene control within the cell experiments. This could be attributed to surface roughness and possible release of residual monomers. Those influences could be investigated in further studies and thus lead to improvement in the additive manufacturing process. In addition, further research focused on the effect of PLA on bone growth should follow. In summary, PLA processed in Fused Deposition Modelling seems to be an attractive material and method for reconstructive surgery because of their biocompatibility and the possibility to produce individually shaped scaffolds

In vitro response of hFOB cells to pamidronate modified sodium silicate coated cellulose scaffolds

The aim of the present study was to evaluate the suitability of cellulose-based scaffolds coated with pure sodium silicate gel and sodium silicate gels accumulated with different concentrations of the bisphosphonate pamidronate as scaffolds for attachment, proliferation and differentiation of human fetal osteoblasts (hFOB 1.19). Human osteoblasts were cultured in vitro for a period up to 14 days on different cellulose scaffolds. Unmodified and sodium silicate coated cellulose scaffolds were used as control. Two surface-coated modifications of cellulose were applied. The scaffolds were coated in a modified two-step dip coating process with pure sodium silicate gel and pamidronate enriched sodium silicate gel, respectively. In order to investigate the influence of the pamidronate, concentrations of 0.667 mg Na-pamidronate/ml sodium silicate solution, 0.333 mg Na-pamidronate/ml sodium silicate solution and 3.33 × 10-3 mg Na-pamidronate/ml sodium silicate solution were used for the coating process. Cell proliferation, vitality and attachment were examined by means of cell counting, WST-1 test, fluorescence and scanning electron microscopy. The relative grade of differentiation of hFOB cells was examined by using quantitative real-time polymerase chain reaction (qRT-PCR) analysis for the gene expression of alkaline phosphatase and osteocalcin. Proliferation and differentiation of human osteoblasts was enhanced by the sodium silicate coatings accumulated with pamidronate compared to pure sodium silicate coatings. There was a reciprocal correlation of vitality with the concentration of pamidronate. The highest vitality was found on surfaces with the lowest pamidronate accumulation. Alkaline phosphatase, an early differentiation marker, was overexpressed after 7 days in cells on all pamidronate-containing surfaces (up to 350% compared to untreated cellulose). Osteocalcin, a late differentiation marker, was overexpressed after 14 days in cells on all coated surfaces (up to 300,000% compared to untreated cellulose). The results indicate that due to the modified coating procedure a homogeneous coating and thus, an enhancement of cell attachment and subsequent cellular functions can be achieved. Low concentrations of pamidronate seem to have a relevant effect on cell proliferation and vitality and, therefore, can be recommended for the improvement of the properties of a biomaterial. © 2008 Elsevier B.V. All rights reserved

Effects of bioactive glass and β-TCP containing three-dimensional laser sintered polyetheretherketone composites on osteoblasts in vitro

Because of their excellent physical properties nonresorbable thermoplastic polymers have become more important for the field of reconstructive surgery. Aim of the present study was to investigate the effects of laser sintered polyetheretherketone (PEEK) with incorporated osteoconductive and bioactive bone substitution materials on osteoblasts in vitro. Human osteoblasts (hFOB 1.19) were seeded onto laser sintered PEEK samples containing nano-sized carbon black, β-tricalciumphosphate (β-TCP), and bioactive glass 45S5. Osteoblasts were investigated for cell viability, cell proliferation and cell morphology. A constant proliferation of osteoblasts could be observed on all samples with the highest values for bioactive glass containing samples at day 7 (OD 1.76 ± 0.22) and day 14 (QD 3.75 ± 0.31) and lowest values for β-TCP containing probes throughout the study compared with the PEEK pure control group. Highest cell viability was observed for Bioglass containing probes (95.5 ± 3.32)% whereas osteoblasts seeded on β-TCP containing probes showed reduced viability (84.4 ± 4.32)%. Laser sintered PEEK implants seem to be attractive candidates for use as bone substitutes for reconstructive surgery because of their biocompatibility, individual shape, and the possibility of compounding bioinert polymer powder with osteoconductive and bioactive materials which might benefit bone formation in vivo. © 2008 Wiley Periodicals, Inc

In vivo performance of osteoactivated cellulose-based scaffolds in bony critical-Size defects

A study was conducted to demonstrate in vivo performance of osteoactivated cellulose-based scaffolds in bony critical-size defects. The study focused on investigating the capacity of a sodium silicate coating applied on knitted cellulose as a long-term depot for a slow drug-release and the incorporation of pamidronate and strontium in sodium silicate coatings. It was observed that the cellulose yarns were randomly ordered according to the knitting patterns. The macropores obtained from the knitting process were filled with resin as they remained open during the coating procedure. The micropores between the monofilaments of the sodium silicate-coated yarn were filled with sodium silicate gel. Scanning electron microscopy (SEM) micrographs also revealed the disappearance of sodium silicate during the whole period of investigation