Biocompatibility of Resorbable Polymers: A Historical Perspective and Framework for the Future.

The history of resorbable polymers containing glycolide, lactide, e-caprolactone and trimethylene carbonate, with a special emphasis being placed on the time frame of the 1960s–1990s is described. Reviewing the history is valuable when looking into the future perspectives regarding how and where these monomers should be used. This story includes scientific evaluations indicating that these polymers are safe to use in medical devices, while the design of the medical device is not considered in this report. In particular, we present the data regarding the tissue response to implanted polymers, as well as the toxicity and pharmacokinetics of their degradation products. In the translation of these polymers from "the bench to the bedside," various challenges have been faced by surgeons, medical doctors, biologists, material engineers and polymer chemists. This Perspective highlights the visionary role played by the pioneers, addressing the problems that occurred on a case by case basis in translational medicine

Inclusion of isolated α-amino acids along the polylactide chain through organocatalytic ring-opening copolymerization

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Endochondral Ossification Induced by Cell Transplantation of Endothelial Cells and Bone Marrow Stromal Cells with Copolymer Scaffold Using a Rat Calvarial Defect Model

It has been recently reported that, in a rat calvarial defect model, adding endothelial cells (ECs) to a culture of bone marrow stromal cells (BMSCs) significantly enhanced bone formation. The aim of this study is to further investigate the ossification process of newly formed osteoid and host response to the poly(L-lactide-co-1,5-dioxepan-2-one) [poly(LLA-co-DXO)] scaffolds based on previous research. Several different histological methods and a PCR Array were applied to evaluate newly formed osteoid after 8 weeks after implantation. Histological results showed osteoid formed in rat calvarial defects and endochondral ossification-related genes, such as dentin matrix acidic phosphoprotein 1 (Dmp1) and collagen type II, and alpha 1 (Col2a1) exhibited greater expression in the CO (implantation with BMSC/EC/Scaffold constructs) than the BMSC group (implantation with BMSC/Scaffold constructs) as demonstrated by PCR Array. It was important to notice that cartilage-like tissue formed in the pores of the copolymer scaffolds. In addition, multinucleated giant cells (MNGCs) were observed surrounding the scaffold fragments. It was concluded that the mechanism of ossification might be an endochondral ossification process when the copolymer scaffolds loaded with co-cultured ECs/BMSCs were implanted into rat calvarial defects. MNGCs were induced by the poly(LLA-co-DXO) scaffolds after implantation, and more specific in vivo studies are needed to gain a better understanding of host response to copolymer scaffolds.publishedVersio

Engineering 3D degradable, pliable scaffolds toward adipose tissue regeneration; optimized printability, simulations and surface modification

We present a solution to regenerate adipose tissue using degradable, soft, pliable 3D-printed scaffolds made of a medical-grade copolymer coated with polydopamine. The problem today is that while printing, the medical grade copolyesters degrade and the scaffolds become very stiff and brittle, being not optimal for adipose tissue defects. Herein, we have used high molar mass poly(L-lactide-co-trimethylene carbonate) (PLATMC) to engineer scaffolds using a direct extrusion-based 3D printer, the 3D Bioplotter®. Our approach was first focused on how the printing influences the polymer and scaffold’s mechanical properties, then on exploring different printing designs and, in the end, on assessing surface functionalization. Finite element analysis revealed that scaffold’s mechanical properties vary according to the gradual degradation of the polymer as a consequence of the molar mass decrease during printing. Considering this, we defined optimal printing parameters to minimize material’s degradation and printed scaffolds with different designs. We subsequently functionalized one scaffold design with polydopamine coating and conducted in vitro cell studies. Results showed that polydopamine augmented stem cell proliferation and adipogenic differentiation owing to increased surface hydrophilicity. Thus, the present research show that the medical grade PLATMC based scaffolds are a potential candidate towards the development of implantable, resorbable, medical devices for adipose tissue regeneration.publishedVersio

Altered surface hydrophilicity on copolymer scaffolds stimulate the osteogenic differentiation of human mesenchymal stem cells

Background: Recent studies have suggested that both poly(l-lactide-co-1,5-dioxepan-2-one) (or poly(LLA-co-DXO)) and poly(l-lactide-co-ε-caprolactone) (or poly(LLA-co-CL)) porous scaffolds are good candidates for use as biodegradable scaffold materials in the field of tissue engineering; meanwhile, their surface properties, such as hydrophilicity, need to be further improved. Methods: We applied several different concentrations of the surfactant Tween 80 to tune the hydrophilicity of both materials. Moreover, the modification was applied not only in the form of solid scaffold as a film but also a porous scaffold. To investigate the potential application for tissue engineering, human bone marrow mesenchymal stem cells (hMSCs) were chosen to test the effect of hydrophilicity on cell attachment, proliferation, and differentiation. First, the cellular cytotoxicity of the extracted medium from modified scaffolds was investigated on HaCaT cells. Then, hMSCs were seeded on the scaffolds or films to evaluate cell attachment, proliferation, and osteogenic differentiation. The results indicated a significant increasing of wettability with the addition of Tween 80, and the hMSCs showed delayed attachment and spreading. PCR results indicated that the differentiation of hMSCs was stimulated, and several osteogenesis related genes were up-regulated in the 3% Tween 80 group. Poly(LLA-co-CL) with 3% Tween 80 showed an increased messenger Ribonucleic acid (mRNA) level of late-stage markers such as osteocalcin (OC) and key transcription factor as runt related gene 2 (Runx2). Conclusion: A high hydrophilic scaffold may speed up the osteogenic differentiation for bone tissue engineering.publishedVersio

Hybrid material based on hyaluronan hydrogels and poly(l-lactide-co-1,3-trimethylene carbonate) scaffolds toward a cell-instructive microenvironment with long-term in vivo degradability

Degradable polyester-based scaffolds are ideal for tissue engineering applications where long-term structural integrity and mechanical support are a requisite. However, their hydrophobic and unfunctionalized surfaces restrain their tissue-mimetic quality. Instead, hyaluronan (HA) hydrogels are able to act as cell-instructive materials with the ability to recapitulate native tissue, although HA is rapidly metabolized in vivo. Taking advantage of these distinctly diverse material properties, a degradable and concurrent hybrid hydrogel material was developed that combines the short-term tissue-relevant properties of bio-orthogonal crosslinked HA with the long-term structural and mechanical support of poly(l-lactide-co-trimethylene carbonate) (PLATMC) scaffolds. This method rendered the formulation of transparent, minimally swelling hydrogel compartments with a desirable cell-instructive “local” elastic modulus within the scaffold matrix without impeding key material properties of PLATMC. Long-term degradability over 180 days in vivo was realized by the integral PLATMC scaffold architecture obtained through either extrusion-based 3D printing or salt-particulate leaching. Intrinsic diffusion capacity within the hydrogel elicited unaffected degradation kinetics of PLATMC in vivo, despite its autocatalytic bulk degradation characteristics displayed when 3D-printed. The effect of the processing method on the material properties of PLATMC markedly extends to its in vivo degradation characteristics, and essential uniform degradation behavior can be advanced using salt-particulate leaching. Regardless of the scaffold fabrication method, the polymer exhibited a soft and flexible nature throughout the degradation period, governed by the rubbery state of the polymer. Our results demonstrate that the physicochemical properties of the hybrid hydrogel scaffold endow it with the potential to act as a cell instructive microenvironment while not affecting key material properties of PLATMC postprocessing. Importantly, the HA hydrogel does not adversely impact the degradation behavior of PLATMC, a vital aspect in the fabrication of tissue engineering constructs. The results presented herein open new avenues for the adoption of concurrent and well-defined tissue-relevant materials exhibiting the potential to recreate microenvironments for cell encapsulation and drug delivery in vivo while providing essential structural integrity and long-term degradability.publishedVersio

Delivery of VEGFA in bone marrow stromal cells seeded in copolymer scaffold enhances angiogenesis, but is inadequate for osteogenesis as compared with the dual delivery of VEGFA and BMP2 in a subcutaneous mouse model

Background: In bone tissue engineering (BTE), extensive research into vascular endothelial growth factor A (VEGFA)-mediated angiogenesis has yielded inconsistent results. The aim of this study was to investigate the influence on angio- and osteogenesis of adenoviral-mediated delivery of VEGFA alone or in combination with bone morphogenetic protein 2 (BMP2) in bone marrow stromal cells (BMSC) seeded onto a recently developed poly(LLA-co-CL) scaffold. Methods: Human BMSC were engineered to express VEGFA alone or in combination with BMP2 and seeded onto poly(LLA-co-CL) scaffolds. Changes in angiogenic and osteogenic gene and protein levels were examined by quantitative reverse-transcription polymerase chain reaction (RT-PCR), PCR array, and alkaline phosphatase assay. An in vivo subcutaneous mouse model was used to investigate the effect on angio- and osteogenesis of VEGFA alone or in combination with BMP2, using microcomputed tomography (μCT), histology, immunohistochemistry, and immunofluorescence. Results: Combined delivery of a lower ratio (1:3) of VEGFA and BMP2 (ad-BMP2 + VEGFA) led to upregulation of osteogenic and angiogenic genes in vitro at 3 and 14 days, compared with mono-delivery of VEGFA (ad-VEGFA) and other controls. In vivo, in a subcutaneous mouse model, both ad-VEGFA and ad-BMP2 + VEGFA scaffold explants exhibited increased angiogenesis at 2 weeks. Enhanced angiogenesis was largely related to the recruitment and differentiation of mouse progenitor cells to the endothelial lineage and, to a lesser extent, to endothelial differentiation of the implanted BMSC. μCT and histological analyses revealed enhanced de novo bone formation only in the ad-BMP2 + VEGFA group, corresponding at the molecular level to the upregulation of genes related to osteogenesis, such as ALPL, RUNX2, and SPP1. Conclusions: Although BMSC expressing VEGFA alone or in combination with BMP2 significantly induced angiogenesis, VEGFA alone failed to demonstrate osteogenic activity both in vitro and in vivo. These results not only call into question the use of VEGFA alone in bone regeneration, but also highlight the importance in BTE of appropriately formulated combined delivery of VEGFA and BMP2.publishedVersio

Comparison of bone regenerative capacity of donor-matched human adipose–derived and bone marrow mesenchymal stem cells

Adipose-derived stem cells (ASC) have been used as an alternative to bone marrow mesenchymal stem cells (BMSC) for bone tissue engineering. However, the efficacy of ASC in bone regeneration in comparison with BMSC remains debatable, since inconsistent results have been reported. Comparing ASC with BMSC obtained from different individuals might contribute to this inconsistency in results. Therefore, this study aimed to compare the bone regenerative capacity of donor-matched human ASC and BMSC seeded onto poly(L-lactide-co-ε-caprolactone) scaffolds using calvarial bone defects in nude rats. First, donor-matched ASC and BMSC were seeded onto the co-polymer scaffolds to evaluate their in vitro osteogenic differentiation. Seeded scaffolds and scaffolds without cells (control) were then implanted in calvarial defects in nude rats. The expression of osteogenesis-related genes was examined after 4 weeks. Cellular activity was investigated after 4 and 12 weeks. Bone formation was evaluated radiographically and histologically after 4, 12, and 24 weeks. In vitro, ASC and BMSC demonstrated mineralization. However, BMSC showed higher alkaline phosphatase activity than ASC. In vivo, human osteogenesis–related genes Runx2 and collagen type I were expressed in defects with scaffold/cells. Defects with scaffold/BMSC had higher cellular activity than defects with scaffold/ASC. Moreover, bone formation in defects with scaffold/BMSC was greater than in defects with scaffold/ASC, especially at the early time-point. These results suggest that although ASC have the potential to regenerate bone, the rate of bone regeneration with ASC may be slower than with BMSC. Accordingly, BMSC are more suitable for bone regenerative applications.publishedVersio

Aliphatic poly(ester)s with thiol pendant groups

The present invention relates to a novel ester monomersusceptible to ring opening polymerization where the monomer comprise a functional group that may be transformedinto thiols or S S groups which allows further functionalization . The present invention also relates to polymers andco - polymers derived from said monomer .QC 20210615</p

Aliphatic poly(ester)s with thiol pendant groups

The present invention relates to a novel ester monomersusceptible to ring opening polymerization where the monomer comprise a functional group that may be transformedinto thiols or S S groups which allows further functionalization . The present invention also relates to polymers andco - polymers derived from said monomer .QC 20210615</p