Segmental long bone regeneration guided by degradable synthetic polymeric scaffolds

doi:10.3877/cma.j.issn.2096-112X.2020.01.004

Biomaterials Translational ›› 2020, Vol. 1 ›› Issue (1): 33-45.doi: 10.3877/cma.j.issn.2096-112X.2020.01.004

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Segmental long bone regeneration guided by degradable synthetic polymeric scaffolds

Xiaowen Xu, Jie Song^*()

Department of Orthopaedics & Physical Rehabilitation, University of Massachusetts Medical School, Worcester, MA, USA.

Received:2020-08-31 Revised:2020-10-26 Accepted:2020-10-29 Online:2020-12-28 Published:2020-12-28
Contact: Jie Song E-mail:Jie.Song@umassmed.edu

Abstract

Abstract:

Recent developments in synthetic bone grafting materials and adjuvant therapeutic agents have opened the door to the regenerative reconstruction of critical-size long bone segmental defects resulting from trauma, osteoporotic fractures or tumour resections. Polymeric scaffolds with controlled macroporosities, degradability, useful surgical handling characteristics, and the ability to deliver biotherapeutics to promote new bone ingrowth have been developed for this challenging orthopaedic application. This review highlights major classes of degradable synthetic polymers and their biomineral composites, including conventional and amphiphilic polyesters, polyanhydrides, polycarbonates, and polyethylene glycol-based hydrogels, that have been explored for the regenerative reconstruction of critical-size long bone segmental defects over the past two decades. The pros and cons of these synthetic scaffold materials are presented in the context of enabling or impeding the functional (mechanical and radiographic) repair of a long bone segmental defect, with the long bone regeneration outcomes compared with healthy long bone controls or results achieved with current grafting standards.

Key words: 3D printing, bone grafting, critical-size defect, hydrogels, long bone segmental defect, synthetic degradable polymers

Cite this article

Figures/Tables 5

Table 1 Degradable synthetic polymeric scaffolds for long bone segmental defects

Graft composition	Animal	Segmental defect	Therapeutics	Regeneration outcomes	Limitations
3D printed PCL/β-TCP composite	SheeP⁴⁴	3 cm tibial	3.5 mg rhBMP-7	Radiographic union; mechanical restoration	Slow graft resorption
PLGA microparticles	SheeP³⁸	2.5 cm femoral	4-mg rhBMP-2	Radiographic union (no mechanical testing)	Tendency of PLGA breakage
PLGA-coated gelatine sponge	Dog³⁹	2.5 cm tibial	0.4 mg/mL rhBMP-2	Radiographic union; mechanical restoration	Small sample size; Bone resorption
Porous PLA-PEG/HAP	Rabbit⁴⁶	1.5 cm radial	5-20 μg rhBMP-2	Radiographic union (no mechanical testing)	Slow graft resorption
PLA-DX-PEG/b-TCP	Rabbit⁴⁷	1.5 cm femoral	50 mg rhBMP-2	Radiographic union; mechanical restoration; full graft resorption	Graft distortion within defect
3D-printed PELGA/HAP	Rat⁵⁴	5 mm femoral	400 ng rhBMP-2/7	Facile & stable graft fixation; rapid union, full graft resorption & mechanical restoration	Larger animal translation unknown
Solid PPF rod/porous sleeve with PLGA microparticle	Rat⁶⁰	5 mm femoral	2-8 μg rhBMP-2	Improved defect fixation by solid rod; improved bone formation	Regeneration impeded by solid rod; no union
Crosslinked PPF/PPF diacrylate with PLGA microparticle	Rabbit⁶¹	1.5 cm radial	200 μg TP508	Improved osteointegration	No union; slow graft resorption
Salicylic acid-based poly(anhydride-ester)/PCL membrane	Rat⁶⁵	5 mm femoral	12 μg rhBMP-2	Ectopic bone formation suppressed; long bone regeneration improved (no mechanical testing)	Poor graft mechanical property; long-term remodelling unclear
Tyrosine-derived polycarbonate/CP	Rabbit⁹⁹	1.5 cm radial	17-35 μg rhBMP-2	Improved bone formation (no mechanical testing)	No union
pHEMA-HAp composite	Rat¹¹⁶	5 mm femoral	400 ng rhBMP-2/7	Radiographic union; mechanical restoration	Slow graft resorption
MMP-sensitive 4-arm PEG hydrogel with integrin binding GFOGER	Murine¹²⁶	2.5 mm radial	30 ng rhBMP-2	Radiographic union; mechanical restoration; MMP-responsive degradation	Potentially high manufacturing cost

Table 1 Degradable synthetic polymeric scaffolds for long bone segmental defects

Graft composition	Animal	Segmental defect	Therapeutics	Regeneration outcomes	Limitations
3D printed PCL/β-TCP composite	SheeP⁴⁴	3 cm tibial	3.5 mg rhBMP-7	Radiographic union; mechanical restoration	Slow graft resorption
PLGA microparticles	SheeP³⁸	2.5 cm femoral	4-mg rhBMP-2	Radiographic union (no mechanical testing)	Tendency of PLGA breakage
PLGA-coated gelatine sponge	Dog³⁹	2.5 cm tibial	0.4 mg/mL rhBMP-2	Radiographic union; mechanical restoration	Small sample size; Bone resorption
Porous PLA-PEG/HAP	Rabbit⁴⁶	1.5 cm radial	5-20 μg rhBMP-2	Radiographic union (no mechanical testing)	Slow graft resorption
PLA-DX-PEG/b-TCP	Rabbit⁴⁷	1.5 cm femoral	50 mg rhBMP-2	Radiographic union; mechanical restoration; full graft resorption	Graft distortion within defect
3D-printed PELGA/HAP	Rat⁵⁴	5 mm femoral	400 ng rhBMP-2/7	Facile & stable graft fixation; rapid union, full graft resorption & mechanical restoration	Larger animal translation unknown
Solid PPF rod/porous sleeve with PLGA microparticle	Rat⁶⁰	5 mm femoral	2-8 μg rhBMP-2	Improved defect fixation by solid rod; improved bone formation	Regeneration impeded by solid rod; no union
Crosslinked PPF/PPF diacrylate with PLGA microparticle	Rabbit⁶¹	1.5 cm radial	200 μg TP508	Improved osteointegration	No union; slow graft resorption
Salicylic acid-based poly(anhydride-ester)/PCL membrane	Rat⁶⁵	5 mm femoral	12 μg rhBMP-2	Ectopic bone formation suppressed; long bone regeneration improved (no mechanical testing)	Poor graft mechanical property; long-term remodelling unclear
Tyrosine-derived polycarbonate/CP	Rabbit⁹⁹	1.5 cm radial	17-35 μg rhBMP-2	Improved bone formation (no mechanical testing)	No union
pHEMA-HAp composite	Rat¹¹⁶	5 mm femoral	400 ng rhBMP-2/7	Radiographic union; mechanical restoration	Slow graft resorption
MMP-sensitive 4-arm PEG hydrogel with integrin binding GFOGER	Murine¹²⁶	2.5 mm radial	30 ng rhBMP-2	Radiographic union; mechanical restoration; MMP-responsive degradation	Potentially high manufacturing cost

Figure 1. Radiographs of a defect treated with polymer-coated gelatin sponge impregnated with recombinant bone morphogenetic protein 2 (0.4 mg/cm3) (anteroposterior view). (A-H) Radiographs were taken at 0 (A), 4 (B), 8 (C), 16 (D and E; before and after plate removal, respectively), 32 (F), 52 (G) and 104 (H) weeks postoperatively. Arrowheads in B and C indicate the hypertrophic bone beyond the metal plate. Reproduced from Kokubo et al.39 with permission from Elsevier.

Figure 2. Representative femoral radiographs. From left, implanted with β-TCP with PLA-DX-PEG and rhBMP-2, β-TCP with PLA-DX-PEG without rhBMP-2, and critical size bone defect without implantation (sham surgery). Sequential radiographs show bone repair at 2, 4, and 8 weeks after implantation in the experimental group. Reproduced from Yoneda et al.47 with permission from Elsevier. DX: p-dioxanone; PEG: poly(ethylene glycol); PLA: poly(lactic acid); rhBMP-2: recombinant bone morphogenetic protein 2; β-TCP: β-tricalcium phosphate.

Figure 3. Accelerated healing of 5-mm rat femoral segmental defects by 25% HAp-PELGA(8/1) grafts preabsorbed with 400-ng rhBMP-2/7. (A) 3D μCT images and BMD colour maps (centre sagittal and axial slices) of the ROI showing maturing regenerated bone within the defect over time. Global thresholding was applied to exclude bone densities below 518.2 mg HAp/cm3 (HAp-PELGA graft invisible at this threshold). (B) Longitudinal μCT quantification of BV and BMD (n ≥ 12) within the ROI over time. Data are presented as means ± SEM. **P < 0.01, ****P < 0.0001 (one-way analysis of variance with Tukey’s post-hoc test). The global lower threshold of 518.2 mg HAp/cm3 was applied for all quantifications. (C) Histological micrographs of H&E-, ALP/TRAP-, and Tol blue-stained sections of explanted graft-filled femurs over time. Scale bars: 1.2 mm (25× magnification) and 300 μm (100× magnification). Boxed regions shown at higher magnification in bottom rows. (D) Boxplots of failure torque and stiffness of intact (control) versus regenerated femur (8/1 + BMP) 16 weeks after being treated with HAp-PELGA(8/1) grafts preloaded with 400-ng rhBMP-2/7 (n = 7). *P < 0.05 (Wilcoxon-Mann-Whitney rank sum test). Reprinted from Zhang et al.54 with permission from AAAS. 3D: three-dimensional; ALP: alkaline phosphatase; BM: bone marrow; BMD: bone mineral density; BMP: bone morphogenetic protein; BV: bone volume; Ctl: control; H&E: haematoxylin and eosin; HAp: hydroxyapatite; HC: healing callus; n.s.: P > 0.05; NB: new bone; PELGA: poly(lactic-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid); rhBMP: human recombinant bone morphogenetic protein; ROI: region of interest; S: scaffold; TRAP: tartrate-resistant acid phosphatase; μCT: micro-computed tomography.

Figure 4. BMP-2 delivery from GFOGER-functionalized gels improves bone regeneration compared to collagen foams. (A) 3D μCT reconstructions of radii (left) and mineral density sagittal sections (right). Scale bar: 1 mm. (B) μCT measures of bone volume in radial defects. (C) Bridging score at 8 weeks post-implantation (n = 13). (D) Maximum torque values for 8 weeks radial samples subjected to torsion mechanical testing to failure (n = 5-9). (E) Sections of 8 weeks radial samples stained with Safranin-O/Fast Green. Scale bar: 200 μm. (F) Retention of infrared dye-labelled BMP-2 at implanted defect sites in vivo (n = 6). (G) Quantification of CD45-/CD90+ osteoprogenitor cells present in the defects 7 days post-implantation (n = 4-6). *P < 0.05, ***P < 0.001, ****P < 0.0001, vs. collagen foam/low dose BMP-2. Reproduced from Shekaran et al.126 with permission from Elsevier. 3D: three-dimensional; BMP-2: bone morphogenetic protein 2; GFOGER: α2β1 integrin-specific hexapeptide sequence Gly-Phe-Hyp-Gly-Glu-Ar; μCT: micro-computed tomography.

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Segmental long bone regeneration guided by degradable synthetic polymeric scaffolds

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