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Comparative histological evaluation of new tyrosine-derived and poly(L-lactic acid) as function of polymer degradation
Abstract
Previous studies demonstrated that poly(DTE carbonate) and poly (DTE adipate), two tyrosine-derived polymers, have suitable properties for use in biomedical applications. This study reports the evaluation of the in vivo tissue response to these polymers in comparison to poly(L-lactic acid) (PLLA). Typically, the biocompatibility of a material is determined through histological evaluations as a function of implantation time in a suitable animal model. However, due to changes that can occur in the tissue response at different stages of the degradation process, a fixed set of time points is not ideal for comparative evaluations of materials having different rates of degradation. Therefore the tissue response elicited by poly(DTE carbonate), poly(DTE adipate), and PLLA was evaluated as a function of molecular weight. This allowed the tissue response to be compared at corresponding stages of degradation. Poly(DTE adipate) consistently elicited the mildest tissue response, as judged by the width and lack of cellularity of the fibrous capsule formed around the implant. The tissue response to poly(DTE carbonate) was mild throughout the 570 day study. However, the response to PLLA fluctuated as a function of the degree of degradation, exhibiting an increase in the intensity of inflammation as the implant began to lose mass. At the completion of the study, tissue ingrowth into the degrading and disintegrating poly(DTE adipate) implant was evident while no comparative ingrowth of tissue was seen for PLLA. The similarity of the in vivo and in vitro degradation rates of each polymer confirmed the absence of enzymatic involvement in the degradation process. A comparison of molecular weight retention, water uptake, and mass loss in vivo with two commonly used in vitro systems [phosphate-buffered saline (PBS) and simulated body fluid (SBF)] demonstrated that for the two tyrosine-derived polymers the in vivo results were equally well simulated in vitro with PBS and SBF. However, for PLLA the in vivo results were better simulated in vitro using PBS.
... Previously, the L-tyrosine-derived polyarylate library ( Figure 2-2) was synthesized and characterized by Kohn and coworkers [9][10][11]. Hooper et al. [12] showed that bone pins made from tyrosine-derived polyarylates are resorbed in vivo without a significant inflammatory response. Currently, a tyrosine-derived polyarylate is used in a FDA approved device for hernia repair [13]. ...
... From the polyarylate library, poly(DTE adipate) has higher in vivo degradation than the equivalent polycarbonate (i.e., poly(DTE carbonate)). Both polymers show random hydrolytic chain cleavage and a very small amount of acidic degradation products [12], in contrast with other polymers like poly(lactic acid) (PLA) (Figure 2-4) that releases carboxylic end groups, provoking autocatalysis of other bonds and acidic degradation by-product generation [16]. Finally, oligomers are released depending on their solubility in the media, and this process drives erosion, which correspond to the mass loss of the polymer. ...
... Also, empirical models have been used to explain water uptake behavior. used an error function to explain the water uptake behavior of a polymer system [189]: (4)(5)(6)(7)(8)(9)(10)(11) while the Peleg equation has been extensively used to explain the water uptake of food systems [131,177,178,[190][191][192][193][194]: (4)(5)(6)(7)(8)(9)(10)(11)(12) where k P1 and k P2 are constant of the model, fitted from the experimental values of water uptake. ...
... In a similar kind of study, Hooper et al. [22] compared the in vivo tissue response of poly(DTE carbonate) and poly(DTE adipate) with PLLA and observed the inflammatory response with the PLLA implant. There are other reports that also showed inflammatory response when PLLA was used in vivo. ...
... Although the same polymer PLLA was used, tissue response differed due to the different architecture of the overall scaffold. Hooper et al. [22] used bulk polymer in the form of a pin with the size of 1.5 cm, whereas nanofibrous mat, which had fibers of 600-700 nm, was used in our study. In addition, the nanofibrous mat was coated with n-HA (50-100 nm) by alternate soaking method [11]. ...
... The relatively lower foreign body reaction was observed with PLLA nanofibers as compared to 3-D porous PLLA scaffold when implanted subcutaneously into the rat for a time period of 4 weeks [29]. Similarly, the microarchitecture and nanoarchitecture could be the prime reasons for the differences in tissue response, which were observed in our study and the study of Hooper et al. [22]. Similar to our study, Matsusue et al. [34] observed no inflammatory or foreign body reaction with PLLA implantation into the medullary cavity of the rabbit femora. ...
In vivo biocompatibility of nanofibrous poly-L-lactic acid (P), poly-L-lactic acid/gelatin (PG), poly-L-lactic acid/hydroxyapatite (PH), and poly-L-lactic acid/gelatin/hydroxyapatite (PGH) scaffolds, useful in regenerative medicine and drug delivery, was evaluated by subcutaneous implantation in both male and female rats (n = 5) for up to 90 days. The body weight of each animal in the study was evaluated on a weekly basis, and no significant difference was noticed. Total and differential leukocyte counts displayed no inflammatory reaction due to scaffold implantation. Gross observation and histology of necropsied vital organs exhibited normal morphology of cell types and tissue, denying any systemic adverse reaction on distal organs. Histology of subcutaneous tissue surrounding scaffolds was done to assess any local toxic effect of implants and found all scaffolds to be compatible and nontoxic. Moreover, no remnant of scaffolds was observed in any of the histological sections, suggesting all scaffolds to be biodegradable. All the results in this study confirm that nanofibrous scaffolds P, PG, PH, and PGH are biocompatible and safe for bone tissue engineering application.
... These results indicate that implantation of PDET elastomers was initially associated with an acute inflammatory response defined by the high amount of leukocytes followed by a chronic inflammatory response as indicated by the remaining cells through the 12 weeks of the study. This response was consistent with the introduction of a foreign material into the body 23,24 and is similar to the immune reactions seen with other absorbable materials, such as cross-linked dermal sheep collagen 25 and tyrosine-derived polymers 26 as well as matrices of poly(lactic acid) and poly(glycolic acid). 27 In those models, the severity of inflammation decreased with the decreasing degradation rate. ...
... These fibrous capsules appeared to become thinner over time in a manner similar to other implanted polymeric absorbable materials. [25][26][27] Ultimately, the disappearance of this collagen layer at the implant site would restore its histological architecture after complete absorption of PDET elastomeric implant, as a classical end stage of fibrous capsules formation. 28 All the above data and observed tissue responses clearly demonstrate that the PDET elastomers are able to coexist with subcutaneous tissues without causing harm, regardless of the time period of implantation and can be considered biocompatible. ...
... However, many of these synthetic materials lack sites for cell adhesion and, therefore, have to be chemically modified to ensure that they will support stem-cell adhesion and culturing [7]. Furthermore, some inflammation responses to synthetic polymers have been observed when the polymers are degraded in vivo [8]. Natural scaffolds have recently received attention because natural polymers such as collagen, fibrin, and silk possess good biocompatibility and biodegradability [9,10]. ...
... After centrifugation at 800 rpm (130 g) for 5 minutes, the supernatant was removed and added to 10 mL of α-MEM. The cell suspensions were seeded in 100-mm culture dishes [8,22]. ...
In this study, we investigated the effect of silk scaffolds on one-wall periodontal intrabony defects. We conjugated nano-hydroxyapatite (nHA) onto a silk scaffold and then seeded periodontal ligament cells (PDLCs) or dental pulp cells (DPCs) onto the scaffold.
Five dogs were used in this study. Bilateral 4 mm×2 mm (depth×mesiodistal width), one-wall intrabony periodontal defects were surgically created on the distal side of the mandibular second premolar and the mesial side of the mandibular fourth premolar. In each dog, four of the defects were separately and randomly assigned to the following groups: the PDLC-cultured scaffold transplantation group (PDLC group), the DPC-cultured scaffold transplantation group (DPC group), the normal saline-soaked scaffold transplantation group, and the control group. The animals were euthanized following an 8-week healing interval for clinical, scanning electron microscopy (SEM), and histologic evaluations.
There was no sign of inflammation or other clinical signs of postoperative complications. The examination of cell-seeded constructs by SEM provided visual confirmation of the favorable characteristics of nHA-coated silk scaffolds for tissue engineering. The scaffolds exhibited a firm connective porous structure in cross section, and after PDLCs and DPCs were seeded onto the scaffolds and cultured for 3 weeks, the attachment of well-spread cells and the formation of extracellular matrix (ECM) were observed. The histologic analysis revealed that a well-maintained grafted volume was present at all experimental sites for 8 weeks. Small amounts of inflammatory cells were seen within the scaffolds. The PDLC and DPC groups did not have remarkably different histologic appearances.
These observations indicate that nHA-coated silk scaffolds can be considered to be potentially useful biomaterials for periodontal regeneration.
... These results indicate that implantation of PDET elastomers was initially associated with an acute inflammatory response defined by the high amount of leukocytes followed by a chronic inflammatory response as indicated by the remaining cells through the 12 weeks of the study. This response was consistent with the introduction of a foreign material into the body 23,24 and is similar to the immune reactions seen with other absorbable materials, such as cross-linked dermal sheep collagen 25 and tyrosine-derived polymers 26 as well as matrices of poly(lactic acid) and poly(glycolic acid). 27 In those models, the severity of inflammation decreased with the decreasing degradation rate. ...
... These fibrous capsules appeared to become thinner over time in a manner similar to other implanted polymeric absorbable materials. [25][26][27] Ultimately, the disappearance of this collagen layer at the implant site would restore its histological architecture after complete absorption of PDET elastomeric implant, as a classical end stage of fibrous capsules formation. 28 All the above data and observed tissue responses clearly ...
Visible light photo-cross-linked biodegradable amorphous elastomers based on poly(decane-co-tricarballylate) (PDET) with different cross-linking densities were synthesized, and their cytotoxicity, biocompatibility, and biodegradability were reported. Cytotoxicity of PDET extracts of the elastomers was assessed for mitochondrial succinate dehydrogenase activity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT assay) and inhibition of [3H] thymidine incorporation into DNA of epithelial cells. The in vivo biocompatibility and biodegradability were determined by subcutaneous implantation of PDET microcylinders in 25 male Sprague–Dawley rats over a period of 12 weeks. The in vivo changes in physical and mechanical parameters of the implants were compared with those observed in vitro. The treated epithelial cells revealed no signs of cytotoxicity, and the elastomer degradation products caused only a slight stimulation to both mitochondrial activity and DNA replication. The implants did not exhibit any macroscopic signs of inflammation or adverse tissue reactions at implant retrieval sites. The retrieved implanted microcylinders maintained their original geometry and extensibility in a manner similar to those observed in vitro. These new elastomers have excellent biocompatibility and are considered promising biomaterials for controlled drug delivery and tissue engineering applications.
... Although the knits were incubated in SBF and the scaffolds in PBS, there was no difference noticed between SBF and PBS PLLA backbone degradation, water uptake or mass loss during the first 27 weeks. 30 When material properties are considered, none of the structures could be preferred over the other, as the maximum load level can be achieved by increasing the amount of material and considering that knits would be used as such in suitable applications under tensile forces. If considering that minimal material usage is preferable, then the 4F-9N knits should be used, of the studied ones, when the mechanical properties are suitable for the purpose of use. ...
... Prior to in vitro incubation or in vivo implantation, the fibers, knits and cylindrical scaffolds were washed with 95% ethanol for 3 minutes in a laboratory-scale ultrasonic washer, dried in vacuum for 24 hours, then packed in vacuum sealed bags (inner layer bag PE, outer layer bag Aluminum/PE for UV-protection) and sterilized by g-irradiation using a commercial procedure, where the minimum dose was set to 25 kGy. The fibers were incubated for periods of 0, 1, 2, 3, 6,9,12,15,18,22,26,30,36 and 42 weeks at 36.5°C in simulated Compression properties of the cylindrical scaffolds were tested using a Lloyd LR 30K Materials Testing Machine (Lloyd Instruments Ltd., Fareham, England). Crosshead speed was 1 mm/min. ...
This study covers the whole production cycle, from biodegradable polymer processing to an in vivo tissue engineered construct. Six different biodegradable polylactide 96/4 L/D single jersey knits were manufactured using either four or eight multifilament fiber batches. The properties of those were studied in vitro for 42 weeks and in 0- to 3-year shelf life studies. Three types (Ø 12, 15 and 19 mm) of cylindrical scaffolds were manufactured from the knit, and the properties of those were studied in vitro for 48 weeks. For the Ø 15 mm scaffold type, mechanical properties were also studied in a one-year in vivo experiment. The scaffolds were implanted in the rat subcutis. All the scaffolds were g-irradiated prior to the studies. In vitro, all the knits lost 99% of their mechanical strength in 30 weeks. In the three-year follow up of shelf life properties, there was no decrease in the mechanical properties due to the storage time and only a 12% decrease in molecular weight. The in vitro and in vivo scaffolds lost their mechanical properties after 1 week. In the case of the in vivo samples, the mechanical properties were restored again, stepwise, by the presence of growing/maturing tissue between weeks 3 and 12. Faster degradation was observed with in vitro scaffolds compared to in vivo scaffolds during the one-year follow up.
... 2,7,8 A variety of synthetic water-insoluble polymers are also being adapted or developed. These include, but are not limited to, poly(lactide), tyrosine-derived polycarbonates (TyrPCs), [9][10][11][12] poly(caprolactone), poly(propylene fumarate) (PPF), [13][14][15] and synthetic hydrogels [e.g., poly(ethylene oxide)based materials]. [16][17][18] The potential advantage of these alternative synthetic scaffolds over allograft is an increase in reproducibility, a reduction in production cost, the potential for custom fabrication to fit the shape of defined defects, and the capacity to be used as a substrate material. ...
... [18][19][20][21] Each laboratory had a history of biomaterials with efficacy in small animals. [9][10][11][12]14,[22][23][24][25][26][27][28] The tested scaffolds are outlined in Table 1, which provides a brief summary of the bulk material, fabrication process, pore geometry, use of calcium containing components, and method of sterilization used in each case. ...
Treatment of large segmental bone defects remains an unsolved clinical challenge, despite a wide array of existing bone graft materials. This project was designed to rapidly assess and compare promising biodegradable osteoconductive scaffolds for use in the systematic development of new bone regeneration methodologies that combine scaffolds, sources of osteogenic cells, and bioactive scaffold modifications. Promising biomaterials and scaffold fabrication methods were identified in laboratories at Rutgers, MIT, Integra Life Sciences, and Mayo Clinic. Scaffolds were fabricated from various materials including: poly(L-lactide-co-glycolide) (PLGA), poly(L-lactide-co-ε-caprolactone) (PLCL), tyrosine-derived polycarbonate (TyrPC), and poly(propylene fumarate) (PPF). Highly porous three dimensional scaffolds were fabricated by three dimensional printing, laser stereolithography, or solvent casting followed by porogen leaching. The canine femoral multi-defect model (CFMD) was used to systematically compare scaffold performance and enable selection of the most promising substrate(s) on which to add cell sourcing options and bioactive surface modifications. Mineralized cancellous allograft (MCA) was used to provide a comparative reference to the current clinical standard for osteoconductive scaffolds. Percent bone volume within the defect was assessed four weeks after implantation using both micro-CT and limited histomorphometry. Bone formed at the periphery of all scaffolds with varying levels of radial ingrowth. MCA produced a rapid and advanced stage of bone formation and remodeling throughout the defect in 4 weeks, greatly exceeding the performance of all polymer scaffolds. Two scaffold constructs, TyrPCPL/TCP and PPF4SLA/HAPLGA Dip proved to be significantly better than alternative PLGA and PLCL scaffolds, justifying further development. Mineralized cancellous allograft remains the current standard for osteoconductive scaffolds.
... The media chosen to perform the degradation studies was PBS. Although this solution does not replicate body fluid (the absence of enzymes that would be present in the host), studies in the past comparing the degradation profiles of polymers in PBS and in vivo found a close match [34][35][36]. ...
The creation of scaffolds for cartilage tissue engineering has faced significant challenges in developing constructs that can provide sufficient biomechanical support and offer suitable degradation characteristics. Ideally, such tissue-engineering techniques necessitate the fabrication of scaffolds that mirror the mechanical characteristics of the articular cartilage while degrading safely without damaging the regenerating tissues. The aim of this study was to create porous, biomechanically comparable 3D-printed scaffolds made from Poly(L-lactide-co-glycolide) 85:15 and to assess their degradation at physiological conditions 37 °C in pH 7.4 phosphate-buffered saline (PBS) for up to 56 days. Furthermore, the effect of scaffold degradation on the cell viability and proliferation of human bone marrow mesenchymal stem cells (HBMSC) was evaluated in vitro. To assess the long-term degradation of the scaffolds, accelerated degradation tests were performed at an elevated temperature of 47 °C for 28 days. The results show that the fabricated scaffolds were porous with an interconnected architecture and had comparable biomechanical properties to native cartilage. The degradative changes indicated stable degradation at physiological conditions with no significant effect on the properties of the scaffold and biocompatibility of the scaffold to HBMSC. Furthermore, the accelerated degradation tests showed consistent degradation of the scaffolds even in the long term without the notable release of acidic byproducts. It is hoped that the fabrication and degradation characteristics of this scaffold will, in the future, translate into a potential medical device for cartilage tissue regeneration.
... Enzymes are confined to the surface and do not affect the molecular weight of the whole implant and only accelerate mass loss. Such a behavior has been observed for PLLA [15]. Since it is possible that the degradation mechanism under enzymatic catalysis differs from purely hydrolytic degradation, our experiments also included PDLLGA degradation under enzymatic catalysis. ...
Poly(lactide-co-glycolide)s are commercially available degradable implant materials, which are typically selected based on specifications given by the manufacturer, one of which is their molecular weight. Here, we address the question whether variations in the chain length and their distribution affect the degradation behavior of Poly[(rac-lactide)-co-glycolide]s (PDLLGA). The hydrolysis was studied in ultrathin films at the air-water interface in order to rule out any morphological effects. We found that both for purely hydrolytic degradation as well as under enzymatic catalysis, the molecular weight has very little effect on the overall degradation kinetics of PDLLGAs. The quantitative analysis suggested a random scission mechanism. The monolayer experiments showed that an acidic micro-pH does not accelerate the degradation of PDLLGAs, in contrast to alkaline conditions. The degradation experiments were combined with interfacial rheology measurements, which showed a drastic decrease of the viscosity at little mass loss. The extrapolated molecular weight behaved similar to the viscosity, dropping to a value near to the solubility limit of PDLLGA oligomers before mass loss set in. This observation suggests a solubility controlled degradation of PDLLGA. Conclusively, the molecular weight affects the degradation of PDLLGA devices mostly in indirect ways, e.g. by determining their morphology and porosity during fabrication. Our study demonstrates the relevance of the presented Langmuir degradation method for the design of controlled release systems.
... 5 However, some inflammation responses to synthetic polymers have been observed when the polymers are degraded in vivo. 6 Metals, either alone or coated with bioactive and bioinert ceramics, have been used for load-bearing orthopedic applications, but problems associated with metal corrosion, ceramics-metal interface wear, and dense fibrous tissue formation on the bone-implant interface may occur. [7][8][9] The use of natural polymers has the potential to limit these drawbacks. ...
In this study, we fabricated a silk scaffold containing nano-hydroxyapatite (nano-HAp) for bone tissue engineering applications. The sericin-extracted silk scaffolds were coated with 0.30, 0.15, and 0.03 g of nano-HAp. The scaffolds were soaked in a 1% type I atelocollagen solution and lyophilized. Scaffolds were crosslinked with 0.02% carbodiimide and lyophilized for 48 h, followed by sterilization with γ-irradiation at 10 kGy. The scaffold properties were investigated by energy-dispersive X-ray spectroscopy and atomic force microscope. A typical spectrum of the inorganic crust and the electron diffraction patterns revealed peaks for calcium, phosphorus, and oxygen atoms. Root mean square values of the control and experimental group surfaces were 5.60 and 40.32 nm. The width of nano-HAp was in the approximate range 100–150 nm, and the height was approximately 350 nm. Dental pulp cells were seeded at a density of 2.8 × 10⁴ cells/cm² and cultured for 3 weeks in a growth medium. The cells were then cultured for 4 weeks in differentiation medium and were transplanted into a nude mouse. The biopsy was processed at 8 weeks. The use of 0.15 g of nano-HAp led to the greatest collagen type III, fibronectin, osteocalcin, osteopontin, osteonectin, osteoprotegerin, and BMP-2 mRNA levels in vitro after 4 weeks in differentiation medium. Western blotting analysis to elucidate signaling pathways was performed. β-Catenin, phosphorylated-ERK, p38 phosphorylation most increased when 0.15 g of nano-HAp was used compared with the control group. In the histological comparison, osteocalcin and osteopontin synthesis were higher for the silk scaffold that contained 0.15 g of nano-HAp. Among the scaffolds, samples containing 0.15 g of nano-HAp were the most effective for osteogenesis. Therefore, this will be a suitable substrate as a biomaterial for bone tissue engineering applications.
... Five device candidates of varying probe and polymer coating sizes were evaluated at six different time points ranging from acute (72 h) to chronic (24 weeks), to determine the effects on the development of the glial scar. The biocompatibility of the polymer used for this work was previously studied [70,74,81,82]. In this study, the size of the polymer coating was shown to affect the glial scar, but there was no statistically significant difference in neuronal loss observed around the implantation sites for any of the probe groups. ...
Objective:
Despite the feasibility of short-term neural recordings using implantable microelectrodes, attaining reliable, chronic recordings remains a challenge. Most neural recording devices suffer from a long-term tissue response, including gliosis, at the device-tissue interface. It was hypothesized that smaller, more flexible intracortical probes would limit gliosis by providing a better mechanical match with surrounding tissue.
Approach:
This paper describes the in vivo evaluation of flexible parylene microprobes designed to improve the interface with the adjacent neural tissue to limit gliosis and thereby allow for improved recording longevity. The probes were coated with an ultrafast degrading tyrosine-derived polycarbonate (E5005(2K)) polymer that provides temporary mechanical support for device implantation, yet degrades within 2 h post-implantation. A parametric study of probes of varying dimensions and polymer coating thicknesses were implanted in rat brains. The glial tissue response and neuronal loss were assessed from 72 h to 24 weeks post-implantation via immunohistochemistry.
Main results:
Experimental results suggest that both probe and polymer coating sizes affect the extent of gliosis. When an appropriate sized coating dimension (100 µm × 100 µm) and small probe (30 µm × 5 µm) was implanted, a minimal post-implantation glial response was observed. No discernible gliosis was detected when compared to tissue where a sham control consisting of a solid degradable polymer shuttle of the same dimensions was inserted. A larger polymer coating (200 µm × 200 µm) device induced a more severe glial response at later time points, suggesting that the initial insertion trauma can affect gliosis even when the polymer shuttle degrades rapidly. A larger degree of gliosis was also observed when comparing a larger sized probe (80 µm × 5 µm) to a smaller probe (30 µm × 5 µm) using the same polymer coating size (100 µm × 100 µm). There was no significant neuronal loss around the implantation sites for most device candidates except the group with largest polymer coating and probe sizes.
Significance:
These results suggest that: (1) the degree of mechanical trauma at device implantation and mechanical mismatches at the probe-tissue interface affect long term gliosis; (2) smaller, more flexible probes may minimize the glial response to provide improved tissue biocompatibility when used for chronic neural signal recording; and (3) some degree of glial scarring did not significantly affect neuronal distribution around the probe.
... To improve degradation properties, PCL-based copolymers have been synthesised [50]. Poly(propylene fumarate), which degrades by hydrolysis of the ester bonds [51] and tyrosine-derived polymers, which show good biocompatibility [52] are being investigated for bone tissue engineering [51,53]. ...
Repairing and regenerating defects of large bones caused by disease or trauma is a significant clinical challenge. Extensive research has been done on bone tissue regeneration incorporating biodegradable scaffolds mainly polymeric scaffolds which are used heavily due to their ease in manufacturing, biocompatibility and biodegradability. The use of biodegradable polymers for scaffolding has certain drawbacks for bone tissue regeneration such as mismatch in mechanical properties and issues relating to bone infection and osseointegration of the bioresorbable scaffold. Metallic foams have been explored as an alternative to polymers as a scaffolding material. Metallic porous structures have advantages such as high strength and ductility relative to polymeric scaffolds that could be favorable for hard tissue regeneration such as bone. In this manuscript, we review metallic scaffolds for bone tissue engineering including potential metals for tissue engineering scaffold applications. Current techniques of metallic scaffold production including production of magnesium scaffold are discussed.
... For this library, the number of oxygen or carbon atoms in the polymer backbone and pendent chain affects properties such as the glass transition temperature (Tg) and the water contact angle. These polymers have been used to fabricate bone pins showing no significant inflammatory response in in vivo resorption studies[39]. Also, drug eluting implants near the eye area have been fabricated[40], as well as FDA approved devices for hernia repair and infection control in 2006[41]. ...
Water has a key role in the functioning of all biological systems, it mediates many biochemical reactions, as well as other biological activities such as material biocompatibility. Water is often considered as an inert solvent, however at the molecular level, it shows different behavior when sorbed onto surfaces like polymeric implants. Three states of water have been recognized: non-freezable water, which does not freeze even at 100 °C; intermediate water, which freezes below 0°C; and, free water, which freezes at 0°C like bulk water. This review describes the different states of water and the techniques for their identification and quantification, and analyzes their relationship with hemocompatibility in polymer surfaces. Intermediate water content higher than 3 wt % is related to better hemocompatibility for poly(ethylene glycol), poly(meth)acrylates, aliphatic carbonyls, and poly(lactic-co-glycolic acid) surfaces. Therefore, characterizing water states in addition to water content is key for polymer selection and material design for medical applications.
... Besides, other environment factors including the addition of drug [140][141][142][143], sterilization [144][145][146][147] and enzymes [148][149][150][151][152][153][154][155][156][157] and so on are reviewed by Alexis [121] and a lot of these facts presented controversial results in so far. ...
Aliphatic biodegradable polyesters have been the most widely used synthetic polymers for developing biodegradable devices as alternatives for the currently used permanent medical devices. The performances during biodegradation process play crucial roles for final realization of their functions. Because physiological and biochemical environment in vivo significantly affects biodegradation process, large numbers of studies on effects of mechanical loads on the degradation of aliphatic biodegradable polyesters have been launched during last decades. In this review article, we discussed the mechanism of biodegradation and several different mechanical loads that have been reported to affect the biodegradation process. Other physiological and biochemical factors related to mechanical loads were also discussed. The mechanical load could change the conformational strain energy and morphology to weaken the stability of the polymer. Besides, the load and pattern could accelerate the loss of intrinsic mechanical properties of polymers. This indicated that investigations into effects of mechanical loads on the degradation should be indispensable. More combination condition of mechanical loads and multiple factors should be considered in order to keep the degradation rate controllable and evaluate the degradation process in vivo accurately. Only then can the degradable devise achieve the desired effects and further expand the special applications of aliphatic biodegradable polyesters.
... Tyrosine-derived: Tyrosine-based derivatives elicit only the mildest tissue response without inflammation [136] and dissolve into naturally occurring metabolites, tyrosine, and PEG within minutes to hours [128,129]. Addition of PEG and dityrosine further enhances control over degradation/dissolution rate. ...
The acquisition of high-fidelity, long-term neural recordings in vivo is critically important to advance neuroscience and brain-machine interfaces. For decades, rigid materials such as metal microwires and micromachined silicon shanks were used as invasive electrophysiological interfaces to neurons, providing either single or multiple electrode recording sites. Extensive research has revealed that such rigid interfaces suffer from gradual recording quality degradation, in part stemming from tissue damage and the ensuing immune response arising from mechanical mismatch between the probe and brain. The development of "soft" neural probes constructed from polymer shanks has been enabled by advancements in microfabrication; this alternative has the potential to mitigate mismatch-related side effects and thus improve the quality of recordings. This review examines soft neural probe materials and their associated microfabrication techniques, the resulting soft neural probes, and their implementation including custom implantation and electrical packaging strategies. The use of soft materials necessitates careful consideration of surgical placement, often requiring the use of additional surgical shuttles or biodegradable coatings that impart temporary stiffness. Investigation of surgical implantation mechanics and histological evidence to support the use of soft probes will be presented. The review concludes with a critical discussion of the remaining technical challenges and future outlook.
... As a model system, a library of Ltyrosine-derived polyarylates was used. Kohn and collaborators used this library to discover promising lead polymers for several medical applications [41], such as bone pins [42], hernia repair devices, and an antibacterial sleeve that protects recipients of implanted cardiac assist devices from potentially life-threatening infections [43]. ...
Prediction of the dynamic properties of water uptake across polymer libraries can accelerate polymer selection for a specific application. We first built semiempirical models using Artificial Neural Networks and all water uptake data, as individual input. These models give very good correlations (
R
2
>
0.78
for test set) but very low accuracy on cross-validation sets (less than 19% of experimental points within experimental error). Instead, using consolidated parameters like equilibrium water uptake a good model is obtained (
R
2
=
0.78
for test set), with accurate predictions for 50% of tested polymers. The semiempirical model was applied to the 56-polymer library of L-tyrosine-derived polyarylates, identifying groups of polymers that are likely to satisfy design criteria for water uptake. This research demonstrates that a surrogate modeling effort can reduce the number of polymers that must be synthesized and characterized to identify an appropriate polymer that meets certain performance criteria.
... The thickness of the capsule and the cellular content at the site of implantation increased slightly at week 4 for both elastomeric implants. After 12 weeks post implantation, these fibrous capsules composed of fibroblasts and fibrous tissue appeared to become thinner in a manner similar to other implanted biodegradable polymers [49][50][51], and the cellular content decreased for all the implants. At the 4th week of implantation, some small fragments from the implanted networks were found on the tissue-implant interface, which was likely due to the erosion of the implants via phagocytosis, these polymeric fragments were absorbed and disappeared gradually with the prolonged degradation time, avoiding the removal of the degradation products from the site of implantation. ...
The degradation of the poly(trimethylene carbonate) (PTMC) and poly(trimethylene carbonate-co-ε-caprolactone) (P(TMC-co-CL)) networks cross-linked by 0.01 and 0.02 mol % 2,2'-bis(trimethylene carbonate-5-yl)-butylether (BTB) was carried out in the conditions of hydrolysis and enzymes in vitro and subcutaneous implantation in vivo. The results showed that the cross-linked PTMC networks exhibited much faster degradation in enzymatic conditions in vitro and in vivo versus in a hydrolysis case due to the catalyst effect of enzymes; the weight loss and physical properties of the degraded networks were dependent on the BTB amount. The morphology observation in lipase and in vivo illustrated that enzymes played an important role in the surface erosion of cross-linked PTMC. The hydrolytic degradation rate of the cross-linked P(TMC-co-CL) networks increased with increasing ε-caprolactone (CL) content in composition due to the preferential cleavage of ester bonds. Cross-linking is an effective strategy to lower the degradation rate and enhance the form-stability of PTMC-based materials.
... We constructed fibrous substrates by electrospinning poly(desaminotyrosyl tyrosine ethyl ester carbonate) (pDTEc), into two architectures, which will be referred to as 'thin' and 'thick' fibre substrates with average fibre diameters of 1.25 ± 0.05 mm and 3.23 ± 0.06 mm, respectively 24 ( Fig. 2a-d). pDTEc is the lead candidate polymer from a combinatorial library of tyrosine-derived polycarbonates 25 , as it effectively supports pluripotent stem cell culture when fabricated into microscale fibrous substrates 24 , and is biocompatible 26 . Similarly, our results with 3D polymeric substrates compared with 2D polymeric substrates suggest that the fibrous architecture governs the longer term cellular behaviours observed in contrast to the polymer composition that plays a role on early interfacial phenomena. ...
Cell replacement therapy with human pluripotent stem cell-derived neurons has the potential to ameliorate neurodegenerative dysfunction and central nervous system injuries, but reprogrammed neurons are dissociated and spatially disorganized during transplantation, rendering poor cell survival, functionality and engraftment in vivo. Here, we present the design of three-dimensional (3D) microtopographic scaffolds, using tunable electrospun microfibrous polymeric substrates that promote in situ stem cell neuronal reprogramming, neural network establishment and support neuronal engraftment into the brain. Scaffold-supported, reprogrammed neuronal networks were successfully grafted into organotypic hippocampal brain slices, showing an â 1/43.5-fold improvement in neurite outgrowth and increased action potential firing relative to injected isolated cells. Transplantation of scaffold-supported neuronal networks into mouse brain striatum improved survival â 1/438-fold at the injection site relative to injected isolated cells, and allowed delivery of multiple neuronal subtypes. Thus, 3D microscale biomaterials represent a promising platform for the transplantation of therapeutic human neurons with broad neuro-regenerative relevance.
... [32][33][34] These events of implant degradation were reported previously with other polymers that were accepted as biocompatible and biodegradable materials. [35][36][37][38] According to macroscopic observations in mice, a loose peripheral connective tissue was formed around all the gel implants, with minimal fibrosis. All the cryogels are porous and have sponge-like characteristics; therefore, implantation of these gels did not induce any dense fibrous capsules, 39,40 which enabled a better vascular invasion of cryogels. ...
Biocompatibility and in vivo degradation are two important characteristics of cell scaffolds. We evaluated these properties for four different polymeric macroporous cryogels, poly-vinylcaprolactam (pVCl), poly-vinyl alcohol-alginate-bioactive glass composite (pTAC), poly-hydroxyethylmethacrylate-gelatin (pHEMA-gelatin) and chitosan-agarose-gelatin (CAG) in mice. All the cryogels were synthesized at sub-zero temperature and were implanted subcutaneously in C57Bl/10.Q inbred mice. Both local and systemic toxicities were negligible as determined by serum TNF- α analysis and histology of surrounding tissues nearby the implants. Complete integration of cryogels into the surrounding tissues with neo-vascular formation was evident in all the mice. At the implantation site, massive infiltration of macrophages and few dendritic cells were observed but neutrophils and mast cells were clearly absent. Macrophage infiltrations were observed even inside the pores of cryogel implants. To ascertain whether oxidative radicals are involved in the cryogel degradation, we implanted these gels in mice deficient for ROS production. Rapid gel degradation was observed in the absence of ROS, and there was no significant difference in the biodegradation of these cryogels between ROS sufficient and deficient mice thereby excluding any major role for ROS in this process. Thus, we demonstrate the biocompatibility and ROS independent biodegradable properties of cryogels that could be useful for tissue-specific tissue engineering applications.
... [32][33][34] These events of implant degradation were reported previously with other polymers that were accepted as biocompatible and biodegradable materials. [35][36][37][38] According to macroscopic observations in mice, a loose peripheral connective tissue was formed around all the gel implants, with minimal fibrosis. All the cryogels are porous and have sponge-like characteristics; therefore, implantation of these gels did not induce any dense fibrous capsules, 39,40 which enabled a better vascular invasion of cryogels. ...
Biocompatibility and in vivo degradation are two important characteristics of cell scaffolds. We evaluated these properties for four different polymeric macroporous cryogels, poly-vinylcaprolactam (pVCl), poly-vinyl alcohol-alginate-bioactive glass composite (pTAC), poly-hydroxyethylmethacrylate-gelatin (pHEMA-gelatin) and chitosan-agarose-gelatin (CAG) in mice. All the cryogels were synthesized at sub-zero temperature and were implanted subcutaneously in C57Bl/10.Q inbred mice. Both local and systemic toxicities were negligible as determined by serum TNF- α analysis and histology of surrounding tissues nearby the implants. Complete integration of cryogels into the surrounding tissues with neo-vascular formation was evident in all the mice. At the implantation site, massive infiltration of macrophages and few dendritic cells were observed but neutrophils and mast cells were clearly absent. Macrophage infiltrations were observed even inside the pores of cryogel implants. To ascertain whether oxidative radicals are involved in the cryogel degradation, we implanted these gels in mice deficient for ROS production. Rapid gel degradation was observed in the absence of ROS, and there was no significant difference in the biodegradation of these cryogels between ROS sufficient and deficient mice thereby excluding any major role for ROS in this process. Thus, we demonstrate the biocompatibility and ROS independent biodegradable properties of cryogels that could be useful for tissue-specific tissue engineering applications.
... 32 In general, these polymers cover a wide range of degradation and resorption rates, 33 a broad range of mechanical properties, 34 and exhibit long-term compatibility with the surrounding tissue. 35 In this study, a specific tyrosine-derived polycarbonate composition (89.5 mol% desaminotyrosyl tyrosine ethyl ester [DTE], 10 mol% desaminotyrosyl tyrosine [DT], and 0.5 mol% of poly(ethylene glycol) [PEG] with Mw of 1 kDa) was evaluated for its potential to enhance nerve regeneration in vitro and in vivo. For brevity, this polymer is designated as E10-0.5(1K). ...
Following complete nerve transection, entubulation of the nerve stumps helps guide axons to reconnect distally. In this study, a biodegradable and non-cytotoxic tyrosine-derived polycarbonate terpolymer composed of 89.5 mol % desaminotyrosyl tyrosine ethyl ester (DTE), 10 mol % desaminotyrosyl tyrosine (DT), and 0.5 mol % poly(ethylene glycol) (PEG, Mw= 1 kDa) (designated as E10-0.5(1K)) was used to fabricate conduits for peripheral nerve regeneration. These conduits were evaluated against commercially available non-porous polyethylene (PE) tubes. The two materials are characterized in vitro for differences in surface properties, and the conduits are then evaluated in vivo in a critical size nerve defect in the mouse femoral nerve model. Conduits were fabricated from E10-0.5(1K) in both porous (P-E10-0.5(1K)) and non-porous (NP-E10-0.5(1K)) configurations. The results illustrate that adsorption of laminin, fibronectin, and collagen type I was enhanced on E10-0.5(1K) compared to PE. In addition, in vivo the E10-0.5(1K) conduits improved functional recovery over PE conduits, producing regenerated nerves with a five-fold increase in the number of axons, and an eight-fold increase in the percentage of myelinated axons. These increases were observed for both P-E10-0.5(1K) and NP-E10-0.5(1K) after 15 weeks. When conduits were removed at 7 or 14 days following implantation, an increase in Schwann cell proteins and fibrin matrix formation was observed in E10-0.5(1K) conduits over PE conduits. These results indicate that E10-0.5(1K) is a pro-regenerative material for peripheral nerves and that the porosity of P-E10-0.5(1K) conduits was inconsequential in this model of nerve injury.
... These materials degrade through hydrolysis of the ester bond in the polymer backbone. Controls of the physical characteristics of the scaffolds, such as fiber diameter, pore size, and polymer crystallinity can regulate the scaffold degradation rates, which can range from 6-8 weeks in the case of highly porous PGA fibrous mesh to 6-18 months in the case of a highly crystalline PLA [11]. Similarly, the mechanical properties of these scaffolds can be regulated and have been shown to range from 5 kPa [12] to 1 GPa [13]. ...
Tissue engineering is a new approach for articular cartilage repair. The aim of the present article was to review the current status of cartilage tissue engineering researches. The scaffold materials used for cartilage tissue engineering, the in vitro, in vivo studies and the clinical trials were all reviewed. Our researches about in vitro cartilage tissue engineering with new type bioactive scaffold and preliminary animal studies results will also be described. The scaffold was tricopolymer made from gelatin, hyaluronan and chondroitin. Chondrocytes seeded in tricopolymer showed in vitro engineered cartilage formation. The engineered cartilage constructs were implanted into knee joints of miniature pigs for animal study.
Peptide-based polymers are evolving as promising materials for various biomedical applications. Among peptide-based polymers, polytyrosine (PTyr)-based and l-tyrosine (Tyr)-derived polymers are unique, due to their excellent biocompatibility, degradability, and functional as well as engineering properties. To date, different polymerization techniques (ring-opening polymerization, enzymatic polymerization, condensation polymerization, solution-interfacial polymerization, and electropolymerization) have been used to synthesize various PTyr-based and Tyr-derived polymers. Even though the synthesis starts from Tyr, different synthesis routes yield different polymers (polypeptides, polyarylates, polyurethanes, polycarbonates, polyiminocarbonate, and polyphosphates) with unique functional characteristics, and these polymers have been successfully used for various biomedical applications in the past decades. This Review comprehensively describes the synthesis approaches, classification, and properties of various PTyr-based and Tyr-derived polymers employed in drug delivery, tissue engineering, and biosensing applications.
Tissue engineering platforms performance an energetic part trendy reformative medication.
Introduction:
Measuring in vivo degradation for polymeric scaffolds is critical for analysis of biocompatibility. Traditionally, histology has been used to estimate mass loss in scaffolds, allowing for simultaneous evaluation of mass loss and the biologic response to the implant. Oxidatively degradable shape memory polyurethane (SMP) foams have been implemented in two vascular occlusion devices: peripheral embolization device (PED) and neurovascular embolization device (NED). This work explores the errors introduced when using histological sections to evaluate mass loss.
Methods:
Models of the SMP foams were created to mimic the device geometry and the tetrakaidekahedral structure of the foam pore. These models were degraded in Blender for a wide range of possible degradation amounts and the mass loss was estimated using m sections.
Results:
As the number of sections (m) used to estimate mass loss for a volume increased the sampling error decreased and beyond m = 5, the decrease in error was insignificant. NED population and sampling errors were higher than for PED scenarios. When m ≥ 5, the averaged sampling error was below 1.5% for NED and 1% for PED scenarios.
Discussion/conclusion:
This study establishes a baseline sampling error for estimating randomly degraded porous scaffolds using a sectional method. Device geometry and the stage of mass loss influence the sampling error. Future studies will use non-random degradation to further investigate in vivo mass loss scenarios.
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, which 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.
This chapter will focus on pathology- and histopathology-based study interactions that will optimize the study design, tissue collection and preparation, and evaluation, interpretation, and documentation of biologic responses to biomaterials and finished medical devices. Much of provided information is also applicable to pathology and histopathology evaluations of combination products (device and pharmaceutical or biologics) and regenerative medicine products that include engineered or polymer scaffolds. The reader should be familiar with and consult the most recent ISO and country-specific regulatory standards and reviews to ensure regulatory compliance with the pathology components of any study.
Magnesium (Mg) and its alloys posse’s great potential for the application of biodegradable
medical implants. It is due to their unique properties like low density and elastic modulus, good
biocompatibility, etc. But still there are many challenges for Mg alloy based implants. Due to
rapid degradation of Mg and its alloys in biological fluid, it loses its mechanical integrity and fails
to perform before the complete healing of bone fracture (in orthopedics application) or removal
of plaque in arteries (in case of vascular implants). Using suitable alloying elements mechanical
strength and corrosion resistance of Mg-alloys can be enhanced but cytotoxicity and long term
inflammatory consequences of these elements are the major concern. Further modifying the
surface characteristics of Mg-alloy through various surface coating, machining, mechanical
working, etc., corrosion behaviour can be manipulated. In this field of biodegradable implants,
the various opportunities are yet to be explored in detail to improve the clinical performance of
Mg alloy implants for orthopedics and vascular applications. This review paper summarises the
various challenges and opportunities in design and development of biodegradable Mg alloy
implants.
For the first time, the N,N-(pyromelitoylimidyl)-bis-(4-hydroxy tyrosine dimethyl ester benzyl sulfonamide) (PHTBS) as diphenolic monomer containing tyrosine was formed in three steps. PHTBS employed as a monomer in the design of biodegradable and biological polymers. The polycondensation of the this monomer with various aromatic and aliphatic diisocyanates such as 4,4′-methylenebis-(4-phenylisocyanate) (a), hexamethylene diisocyanate (b), isophorone diisocyanate (c) and toluene-2,4-diisocyanate (d) was carried out under traditional polymerization conditions to give poly(urethane-imide-sulfonamide)s (PUIS)s as pseudo-poly(amino acid)s (PAAs). The novel PHTBS and obtained PUISs were characterized with FTIR, ¹³C-NMR, ¹H-NMR spectroscopy, X-ray diffraction (XRD), field emission scanning electron microscopy and elemental analysis. Differential scanning calorimetry and thermogravimetric analysis were used to determine the thermal properties of the polymers. Morphology probes showed these PUISs were nanoshape polymers. On the basis of thermogravimetric analysis data, such PUISs are thermally stable and can be classified as self-extinguishing polymers. The obtained PUISs possessed more bioactivity, moderate thermal stability and high solubility in common organic solvents. Furthermore, soil enzymatic of the PHTBS and the obtained PUISs assay showed that the synthetic materials are biologically active and then could be classified as bioactive and biodegradable compounds.
Synthetic biodegradable polymers are widely used in medicine and biology and are essential components of drug delivery vehicles, tissue engineering scaffolds, and biomedical devices. There is, therefore, great interest in designing new synthetic biodegradable polymers for biomedical applications. A key property that controls the function and effectiveness of biomedical polymers is their rate of degradation. In this chapter, we will describe the physical and chemical mechanisms by which the major classes of biomedical polymers degrade. In particular, the hydrolysis of polyesters, polyanhydrides, polyorthoesters, and polyketals is discussed. The hydrolysis of these polymers by water is described, and the factors that influence their water hydrolysis rates are also discussed, such as catalysis of hydrolysis by acid, base, and enzymes. In addition, the physical factors that influence polymer hydrolysis rates will also be described, such as polymer crystallinity and hydrophobicity. We anticipate that this information will provide the basis for predicting the hydrolysis kinetics of synthetic polymers and will assist in the design of new polymers for biomedical applications.
Poly(lactic acid) (PLA) has received increasing attentions in the development of shape memory polymers (SMPs) due to its excellent physical properties and good biocompatibility. However, the intrinsically increased crystallinity of PLA at higher deformation ratios still remains as a significant challenge, which remarkably restricts the chain mobility and reduces shape recovery efficiency. Being different from other types of biodegradable polymers, the diverse isomeric forms of PLA have provided great opportunities for modulation of PLA towards a favourable property by incorporating different PLA stereoisomers in one macromolecular architecture. In this paper, we report a completely amorphous PLA poly(ester urethane) elastomer that exhibits excellent shape fixity (>99%) and shape recovery (>99%) in a time frame of seconds. By means of adjusting the stereoisomeric ratios and control over architecture, the resultant poly(PLLA/PDLLA urethane)s (PLDU) elastomers show a single glass transition temperature ( Tg), as the only thermal event, in the range of 38 – 46 °C in a predictable manner. The elastic moduli of PLDU elastomers display a 100-fold loss during the sharp transition from glassy to rubbery state with temperature alternation across their corresponding Tg, indicating a successful manipulation of the thermo-mechanical properties by temperature as required in thermally induced SMPs. In addition, all samples display a typical elastomeric behaviour with elongation at break (εb) greater than 400%. The effect of the stereoisomer content on the tensile modulus and elastic mechanical behaviour were also systematically investigated. Together with the prominent degradation property, the new PLDU elastomers developed in this study show great potential for biomedical applications as shape memory implants.
Tissue engineering has shown great promise in developing novel therapies for treating injured tissue and organ failure. Scaffolds play a pivotal role in tissue engineering. Biodegradable polymers are the primary choice of material for tissue engineering scaffolds, due to their numerous advantageous properties. In this article, the principles of tissue engineering are discussed in relation to polymer science and engineering. The most frequently used polymers in tissue engineering are briefly reviewed. These include synthetic and natural polymers commonly used in constructing both porous and hydrogel scaffolds. Their structure and critical properties in relation to scaffold function are discussed in depth, along with a detailed review of the important roles functionalized materials and controlled release play in tissue engineering. Important polymer processing techniques in the context of scaffold fabrication are also reviewed. These include the textile technologies, electrospinning, particulate-leaching techniques, phase-separation techniques, rapid prototyping, and other novel three-dimensional (3D) fabrication techniques. In this update, the impact of pluripotent stem cells, conductive polymers, controlled drug release, 3D printing, and nanofibrous topology on tissue engineering are also discussed.
There are many different resorbable polymer systems based on different degradation mechanisms, and having a range of physical and mechanical properties. This chapter covers those polymers that are fiber forming and hydrolytically sensitive. Mechanical properties, resorption profile, and medical applications for these polymers have been discussed.
Background:
Meniscus injuries and resulting meniscectomies lead to joint deterioration, causing pain, discomfort, and instability. Tissue-engineered devices to replace the meniscus have not shown consistent success with regard to function, mechanical integrity, or protection of cartilage.
Purpose:
To evaluate a novel resorbable polymer fiber-reinforced meniscus reconstruction scaffold in an ovine model for 52 weeks and assess its integrity, tensile and compressive mechanics, cell phenotypes, matrix organization and content, and protection of the articular cartilage surfaces.
Study design:
Controlled laboratory study.
Methods:
Eight skeletally mature ewes were implanted with the fiber-reinforced scaffold after total meniscectomy, and 2 additional animals had untreated total meniscectomies. Animals were sacrificed at 52 weeks, and the explants and articular surfaces were analyzed macroscopically. Explants were characterized by ultimate tensile testing, confined compression creep testing, and biochemical, histological, and immunohistochemical analyses. Cartilage damage was characterized using the Mankin score on histologic slides from both the femur and tibia.
Results:
One sheep was removed from the study because of a torn extensor tendon; the remaining 7 explants remained fully intact and incorporated into the bone tunnels. All explants exhibited functional tensile loads, tensile stiffnesses, and compressive moduli. Fibrocartilagenous repair with both types 1 and 2 collagen were observed, with areas of matrix organization and biochemical content similar to native tissue. Narrowing in the body region was observed in 5 of 7 explants. Mankin scores showed less cartilage damage in the explant group (femoral condyle: 3.43 ± 0.79, tibial plateau: 3.50 ± 1.63) than in the meniscectomy group (femoral condyle: 8.50 ± 3.54, tibial plateau: 6.75 ± 2.47) and were comparable with Mankin scores at the previously reported 16- and 32-week time points.
Conclusion:
A resorbable fiber-reinforced meniscus scaffold supports formation of functional neomeniscus tissue, with the potential to prevent joint degeneration that typically occurs after total meniscectomy. Further studies with improvements to the initial mechanics of the scaffold and testing for longer time periods are warranted.
Clinical relevance:
Meniscectomy is an extremely common orthopaedic procedure, and few options currently exist for the treatment of significant loss of meniscus tissue. Successful development of a tissue-engineered meniscus scaffold could substantially reduce the incidence of postmeniscectomy joint degeneration and the subsequent procedures used for its treatment.
The strategic importance of polymers became evident during the Second World War through the invention of artificial rubber and led to the establishment of highly productive applied polymer research groups in industry and academe. Concurrently, polymer science, long viewed in academe as plebian technology that was unworthy of academic consideration, became a fully recognized research focus in many traditional research universities, with exciting new discoveries ranging from controlled, self-assembling molecular architectures to polymer based electronic and photonic devices. These discoveries are adding new dimensions to the potential utility of macromolecules. These issues are especially relevant for very high performance polymers, such as continuous fiber reinforced composites, materials designed for use under conditions of environmental extremes, and parts that need to function reliably for extended periods of time. Understanding of the interrelationships of processing, properties, and structure is the cornerstone of modern material science.
Synthetic biodegradable polymers are widely used in medicine and biology and are essential components of drug delivery vehicles, tissue engineering scaffolds, and biomedical devices. There is, therefore, great interest in designing new synthetic biodegradable polymers for biomedical applications. A key property that controls the function and effectiveness of biomedical polymers is their rate of degradation. In this review article, we will describe the physical and chemical mechanisms by which the major classes of biomedical polymers degrade. In particular, the hydrolysis of polyesters, polyanhydrides, polyorthoesters, and polyketals is discussed. The hydrolysis of these polymers by water is described, and the factors that influence their water hydrolysis rates are also discussed, such as catalysis of hydrolysis by acid, base, and enzymes. In addition, the physical factors that influence polymer hydrolysis rates will also be described, such as polymer crystallinity and hydrophobicity. We anticipate that this information will provide the basis for predicting the hydrolysis kinetics of synthetic polymers and will assist in the design of new polymers for biomedical applications.
The objective of the present in vitro study was to determine vascular endothelial and smooth muscle cell responses to poly(lactic-co-glycolic acid) (PLGA) films that were exposed apriori to various degrees of alkaline degradation. To model the alkaline environment of blood in arteries, PLGA films were separately soaked in select concentrations (from 0.1 - 10 N) of NaOH for various periods of time (from 10 minutes to 1 hour). Vascular endothelial and smooth muscle cells were then separately allowed to adhere and/or proliferate on the different PLGA degraded surfaces. Results provided the first evidence that smooth muscle adhesion and proliferation increased with larger amounts of alkaline PLGA degradation. In contrast, endothelial cell adhesion and proliferation decreased with increasing amounts of alkaline PLGA degradation. In this manner, the present in vitro study suggests a possible mechanism for insufficient endothelialization on PLGA vascular implants in vivo.
Tissue engineering, still in its infancy, has shown great promise in developing novel therapies to tissue losses and organ failures. Scaffolds play a pivotal role in tissue engineering. Biodegradable polymers are the primary choice of materials for tissue engineering scaffolds. In this article, the principles of tissue engineering are discussed in relation to polymer science and engineering. The most frequently used polymers in tissue engineering are briefly reviewed. These include synthetic and natural polymers for porous scaffolds and hydrogel scaffolds. Their structure and important properties in relation to scaffold function are discussed. Important polymer processing techniques in the context of scaffold fabrication are also reviewed. These include the textile technologies, particulate-leaching techniques, phase separation techniques, rapid prototyping, and other novel 3-D fabrication techniques.
Mathematical models of controlled release that span the in vitro to in vivo transition are needed to speed the development and translation of clinically-relevant controlled release drug delivery systems. Fully mechanistic approaches are often challenged due to the use of highly-parameterized mathematically complex structures to capture the release mechanism. The simultaneous scarcity of in vivo data to inform these models and parameters leads to a situation where overfitting to capture observed phenomena is common. A data-driven approach to model development for controlled drug release from polymeric microspheres is taken herein, where physiological mechanisms impacting controlled release are incorporated to capture observed changes between in vitro release profiles and in vivo device dynamics. The model is generalizable, using non-specific binding to capture drug-polymer interactions via charge and molecular structure, and it has the ability to describe both inhibited (slowed) and accelerated release resulting from electrostatic or steric interactions. Reactive oxygen species (ROS)-induced degradation of biodegradable polymers was incorporated via a reaction-diffusion formalism, and this suggests that ROS may be the primary effector of the oft-observed accelerated in vivo release of polymeric drug delivery systems. Model performance is assessed through comparisons between model predictions and controlled release of several drugs from various-sized microparticles in vitro and in vivo.
Copyright © 2015. Published by Elsevier B.V.
A series of amino-acid based poly(ester urea)s (PEU) with controlled amounts of branching was synthesized and characterized. The mechanical properties, thermal characteristics and water absorptions varied widely with the extent of branch unit incorporation. Herein, the details of the synthesis of a linear bis(L-phenylalanine)-hexane 1,6-diester monomer, a branch triO -benzyl-L-tyrosine-1,1,1-trimethylethane triester monomer and a series of copolymers are described. The extent of branching was varied by adjusting the molar ratio of linear to branched monomer during the interfacial polymerization. The elastic moduli span a range of values (1.0−3.1 GPa) that overlaps with several clinically available degradable polymers. Increasing the amount of branching monomers reduces the molecular entanglement, which results in a decrease in elastic modulus values and an increase in values of elongation at break. The L-phenylalanine-based poly(ester urea)s also exhibited a branch density dependent water uptake ability that varied between 2 and 3% after 24 h of immersion in water. Nanofibers incorporating 8% branching were able to maintain their morphology at elevated temperature, in hydrated conditions, and during ethylene oxide sterilization which are critical to efforts to translate these materials to clinical soft tissue applications.
Two self-reinforced poly(desamino tyrosyl–tyrosine ethyl ester carbonate), poly(DTE carbonate) or self-reinforced poly(DTE carbonate)/bioactive glass rods, (2 mm by 40 mm) were implanted into the dorsal subcutaneous tissue and osteotomies of the distal femur were fixed with these rods (2 mm by 26 mm) in 36 rabbits. The follow-up times varied from three to 100 weeks. After sacrifice, three-point bending and shear tests and molecular weight measurements were performed for subcutaneously placed rods. Radiological, histological, histomorphometrical, microradiographic, and oxytetracycline-fluorescence studies of the osteotomized and intact control femora were performed. The initial mechanical properties were higher with the SR-poly(DTE carbonate) rods, but the SR-poly(DTE carbonate)/bioactive glass rods lost their mechanical properties slower. At 100 weeks the bending strength had decreased to 21% of the initial value with the SR-poly(DTE carbonate) rods and to 49% with the SR-poly(DTE carbonate)/bioactive glass rods. The shear strength had decreased to 10% with the SR-poly(DTE carbonate) rods and to 23% of the initial value with the SR-poly(DTE carbonate)/bioactive glass rods. Two slight displacements and one delayed union and one failure of fixation were seen in the SR-poly(DTE carbonate) group. In the SR-poly(DTE carbonate)/bioactive glass group five delayed unions and seven slight displacements were seen. No signs of osteolysis or foreign body reactions were observed. Signs of resorption of the implants were seen at 100 weeks in the SR-poly(DTE carbonate)/bioactive glass group. The present investigation showed that the mechanical strength and fixation properties of SR-poly(DTE carbonate) and SR-poly(DTE carbonate)/bioactive glass rods are suitable for fixation of cancellous bone osteotomies in rabbits.
We report a fabrication process for coating neural probes with an ultrafast degrading polymer to create consistent and reproducible devices for neural tissue insertion. The rigid polymer coating acts as a probe insertion aid, but resorbs within hours post-implantation. Despite the feasibility for short term neural recordings from currently available neural prosthetic devices, most of these devices suffer from long term gliosis, which isolates the probes from adjacent neurons, increasing the recording impedance and stimulation threshold. The size and stiffness of implanted probes have been identified as critical factors that lead to this long term gliosis. Smaller, more flexible probes that match the mechanical properties of brain tissue could allow better long term integration by limiting the mechanical disruption of the surrounding tissue during and after probe insertion, while being flexible enough to deform with the tissue during brain movement. However, these small flexible probes inherently lack the mechanical strength to penetrate the brain on their own. In this work, we have developed a micromolding method for coating a non-functional miniaturized SU-8 probe with an ultrafast degrading tyrosine-derived polycarbonate (E5005(2 K)). Coated, non-functionalized probes of varying dimensions were reproducibly fabricated with high yields. The polymer erosion/degradation profiles of the probes were characterized in vitro. The probes were also mechanically characterized in ex vivo brain tissue models by measuring buckling and insertion forces during probe insertion. The results demonstrate the ability to produce polymer coated probes of consistent quality
for future in vivo use, for example to study the effects of different design parameters that may affect tissue response during long term chronic intra-cortical microelectrode neural recordings.
A new class of l-phenylalanine-based poly(ester urea)s (PEU) was developed that possess tunable mechanical properties and degradation rates. Our preliminary data have shown that 1,6-hexanediol-l-phenylalanine-based poly(ester urea)s possess an elastic modulus nearly double that of poly(lactic acid). The data in this article detail the synthesis of a series of l-phenylalanine-based poly(ester urea)s possessing a variation in diol chain length and how these subtle structural differences influence the mechanical properties and in vitro biodegradation rates. The mechanical data span a range of values that overlaps with several currently clinically available degradable polymers. Increasing the diol chain lengths increases the amount of flexible segment in the chemical structure, which results in reduced elastic modulus values and increased values of elongation at break. The l-phenylalanine-based poly(ester urea)s also exhibited a diol length dependent degradation process that varied between 1 and 5% over 16 weeks. Compared with PLLA, PEUs degrade more quickly, and the rate can be tuned by changing the diol chain length.
The performance of biodegradable polymeric systems strongly depends on their physical as well as on their chemical properties. Therefore, detailed chemical analysis of such systems is essential. Enzymatic and chemical hydrolysis are the primary biodegradation mechanisms for these materials. This review provides an overview of the strategies and analytical methods used for the structural and compositional chemical analysis of nondegraded, partially degraded, and fully degraded synthetic polymeric biomaterials with an emphasis on modern solution-based techniques that yield large amounts of information. The degradation methods that facilitate the study of polymeric networks are also described.
Polycarbonate terpolymers consisting of desaminotyrosyl-tyrosine alkyl esters (DTR), desaminotyrosyl-tyrosine (DT), and low molecular weight blocks of poly(ethylene glycol) (PEG) are a new class of polymers that have good engineering properties while also being resorbable in vivo. This study is the first evaluation of their (i) degradation behavior, (ii) in vitro cytotoxicity, and (iii) in vivo biocompatibility. Porous, tissue engineering scaffolds were prepared by a combination of solvent casting, porogenleaching and phase separation techniques. The scaffolds (>90% porosity) displayed (i) a bimodal pore distribution with micropores of less than 20 µm and macropores between 200 and 400 µm, (ii) a highly interconnected and open pore architecture, and (iii) a highly organized microstructure where the micropores are oriented and aligned along the walls of the macropores. Molecular weight (number average, Mn) and mass loss were determined in vitro (PBS at 37 °C) for up to 28 days. All three terpolymer compositions were fast degrading and retained only 10% of their initial molecular weight after 21 days, while mass loss during the 28 days was polymer composition-dependent. In vitro biocompatibility of the polymer scaffolds was determined up to 14 days by measuring metabolic activity of MC3T3.E1 (subclone 4) pre-osteoblasts. The outcome showed no statistical difference between cells cultured in monolayer and all tested polymer scaffolds. Robust cell attachment throughout the scaffold volume was observed by confocal microscopy and SEM. The biocompatibility of resorbing scaffolds was evaluated at 12 week in a critical sized defect (CSD) rabbit calvaria model and showed only a minimal inflammatory response. Overall, the results reported here illustrate the potential utility of tyrosine-derived polycarbonate terpolymers in the design of tissue engineering scaffolds.
Tissue engineering is an interdisciplinary and multidisciplinary field. It has shown great promise in generating living alternatives for harvested tissues and organs for transplantation and reconstructive surgery. Materials and fabrication technologies are critically important for tissue engineering in designing temporary, artificial extracellular matrices (scaffolds), which support three-dimensional tissue formation. This review briefly introduces the concept of tissue engineering, and illustrates the relationship between tissue engineering and materials science and engineering. Important scaffold design principles are described. The most frequently used materials and fabrication technologies for scaffolds are reviewed. Some exciting new developments in scaffold materials and fabrication technologies are also discussed.
Tlyrosine-derived polycarbonates and polyarylates have recently been recognized as promising biomaterials. In these novel polymers, non-toxic desaminotyrosyl-tyrosine alkyl esters are being used as monomers in place of industrial diphenols such as Bisphenol A. The high cost and limited availability of desaminotyrosyl-tyrosine alkyl esters have prevented the large-scale preparation of these polymers. To address this problem, the following four peptide coupling techniques were explored: dicyclohexylcarbodiimide with 1-hydroxybenzotriazole hydrate (DCC/HOBt), ethyl-3-(3-dimethylamino)propyl carbodiimide hydrochloride salt (EDCI-HCl), N-hydroxysuccinimide (NHS) active ester, and p-nitrophenol (pNP) active ester. Desaminotyrosyl-tyrosine hexyl ester (DTH) was used as a model compound. DCC/HOBt led to a crude product that required column chromatography for purification. The water soluble coupling agent EDCI-HCl made it possible to replace column chromatography by precipitation/extraction in aqueous media. This alleviated possible environmental concerns about the use of organic solvents. Furthermore, EDCI-HC1 did not require the addition of an auxiliary nucleophile such as HOBt in the reaction mixture, The use of the NHS active ester of Dat also produced DTH of sufficient purity, but was less cost effective than EDCI-HCI. The pNP active ester produced YIH which could not be easily purified. Based on these results, the effectiveness of EDCI-HCI was verified by the 100 g synthesis of the ethyl, butyl, hexyl and octyl esters of desaminotrosyl-tyrosine. All of these monomers could be polymerized to high polymers. Overall, the EDCI-HCl mediated coupling of Dat and tyrosine alkyl esters was identified as the best method for the large-scale synthesis of the desaminotyrosyl-tyrosine alkyl esters in a cost efficient and environmentally acceptable manner.
This study focuses on examining the biological response of intramedullary bone to poly-L-lactic acid (PLLA), particularly during the PLLA degradation phase. To study the influence of spherical crystals (spherulites) of PLLA on intramedullary bone response, two different types of PLLA coupon, with and without spherulites but with the same molecular weight, were used. Chambers containing PLLA coupons were implanted into the right femur of eight dogs, four with and four without spherulites; chambers containing stainless steel (SS) coupons (as a control) were implanted in the left femurs of all eight. Two dogs, one with and one without spherulites, were sacrificed at 3, 6, 12, and 24 weeks postoperatively. Histomorphometric evaluation and histophathological assessment were used to compare the response to PLLA and SS. Scanning electron micrographs showed that there were minimal changes in the surface of PLLA coupons at 3 and 6 weeks. But at 12 and 24 weeks, there were many cracks and holes on the surfaces of the coupons, and some parts of the surface were scaling off. The cross-sectional area of PLLA coupons showed no change at 3 and 6 weeks, but started to decrease by 12 weeks. The amount of ingrown bone between PLLA coupons was significantly greater than that between SS coupons at 3 and 6 weeks, but had decreased dramatically by 12 weeks. Extensive bone resorption around PLLA coupons occurred by 12 weeks accompanied by infiltration of inflammatory cells. An abundance of histiocytes, giant cells, and leucocytes were seen, along with a few histiocytes that had phagocytized PLLA particles of less than 2 μm. By contrast, no inflammatory reaction was seen in SS samples at any period up to and including 24 weeks. PLLA demonstrated excellent biocompatibility with intramedullary bone for the first 6 weeks in this model. Once degradation commenced, however, biocompatibility decreased dramatically. Our study detected no difference between coupons with and without spherulites. It thus appears that the existence of relatively large PLLA particles did not influence the response of intramedullary bone to PLLA, but rather that it was the smaller particles (< 2 μm) released from the PLLA that induced foreign-body inflammatory reactions and bone resorption. It is also possible that a local decrease in pH occurred around PLLA coupons, which could have influenced vital kinetics. © 1993 John Wiley & Sons, Inc.
Tyrosine-derived polycarbonates are a new class of degradable polymers developed for orthopedic applications. In this study the long-term (48 week) in vivo degradation kinetics and host bone response to poly(DTE carbonate) and poly(DTH carbonate) were investigated using a canine bone chamber model. Poly(L-lactic acid) (PLA) served as a control material. Two chambers of each test material were retrieved at 6-, 12-, 24-, and 48-week time points. Tyrosine-derived polycarbonates were found to exhibit degradation kinetics comparable to PLA. Each test material lost approximately 50% of its initial molecular weight (Mw) over the 48-week test period. Poly(DTE carbonate) and poly(DTH carbonate) test chambers were characterized by sustained bone ingrowth throughout the 48 weeks. In contrast, bone ingrowth into the PLA chambers peaked at 24 weeks and dropped by half at the 48-week time point. A fibrous tissue layer was found surrounding the PLA implants at all time points. This fibrous tissue layer was notably absent at the interface between bone and the tyrosine-derived polycarbonates. Histologic sections revealed intimate contact between bone and tyrosine-derived polycarbonates. From a degradation-biocompatibility perspective, the tyrosine-derived polycarbonates appear to be comparable, if not superior, to PLA in this canine bone chamber model. © 1996 John Wiley & Sons, Inc.
Tyrosine-derived polycarbonates are a new class of degradable polymers that have possible biomedical applications. In this study, the effect of the two most common sterilization techniques, ethylene oxide and γ-irradiation (0.3, 1.1, 3.9, 6.4, 10.6 Mrad), was evaluated for a family of four structurally related tyrosine-derived polycarbonates and for poly(L-lactic acid) (PLLA). The four polycarbonates were poly(DTE carbonate), poly(DTB carbonate), poly(DTH carbonate), and poly(DTO carbonate) and differed only in the length of the pendent chain. Ethylene oxide exposure had little effect on molecular weight, surface composition, mechanical properties, or degradation rate of all test polymers except for poly(DTO carbonate). Poly(DTO carbonate) was unique since following ethylene oxide exposure it degraded faster than did the nonsterilized control. γ-Irradiated tyrosine-derived polycarbonates retained over 81% of their initial molecular weight when exposed to a clinically relevant dose of 3.9 Mrad and retained still 58% of the initial molecular weight when exposed to the highest test dose of 10.6 Mrad. No changes in surface composition and only slight changes in yield strength and the Young's modulus were detected for any of the tyrosine-derived polycarbonates following γ-irradiation. In vitro, irradiated films of poly(DTE carbonate), poly(DTB carbonate), and poly(DTH carbonate) degraded at approximately the same rate as did the nonsterilized films regardless of irradiation dose. Only poly(DTO carbonate), irradiated at high doses, degraded faster than did the control. Medical-grade PLLA was tested under identical conditions. Ethylene oxide exposure of PLLA did not affect the molecular weight, surface composition, mechanical properties, or in vitro degradation rate. However, upon irradiation at 10.6 Mrad, PLLA retained only 29% of its initial molecular weight; a dose of 3.9 Mrad resulted in retention of 49% of the initial molecular weight. In correspondence with earlier publications, irradiation of PLLA induced significant losses in the Young's modulus, % strain at break, and changes in the postirradiation rate of degradation in some specimens. Compared to PLLA, tyrosine-derived polycarbonates are significantly more stable to γ-irradiation and can be sterilized by conventional γ-sterilization techniques. © 1997 John Wiley & Sons, Inc. J Appl Polym Sci 63: 1499–1510, 1997
An in vivo method is described for screening polymeric materials for biocompatibility. The test is based on grading acute and subacute tissue reactions at 7 and 28 days, respectively, following implantation in rats. The methods is reproducible and reliable. It is designed to provide uniform test criteria for biocompatibility assessment in the early phases of the development of surgical implant materials.
The breeding and maintenance conditions for 2 strains of inbred rats, the WAG/Rij and BN/Bi rats, were described. The survival characteristics of these 2 strains were compared with those of 2 other experiments in which rats were kept for longevity studies under different environmental conditions of microbiologic status and diet. Data were provided on the rate and types of spontaneous tumors found in these 2 rat strains. It can be concluded that in order to obtain rats of good quality and in sufficient numbers for aging studies, breeding and raising the animals under strict SPF conditions is warranted. It is also necessary to maintain them under "clean conventional" conditions for long-term studies.
The gradual shift from biostable prostheses to degradable, temporary implants represents one of the most significant trends in biomaterials research. In view of this trend, medical applications of degradable implant materials were reviewed with special emphasis on orthopedic polymeric implants. Among the polymeric implant materials derived from natural sources, collagen, various polysaccharides such as cellulose, and microbial polyesters have been intensively investigated. Among the synthetic, degradable polymers, aliphatic polyesters such as poly(glycolic acid), poly(lactic acid), poly(caprolactone) and polydioxanone, are most commonly investigated. Only recently, several new classes of polymers such as poly(ortho esters), polyanhydrides, and degradable polycarbonates have been introduced as potential implant materials. A particularly versatile group of new biomaterials with promising engineering properties are the "pseudo"-poly(amino acids), amino acid derived polymers in which conventional peptide bonds have been replaced by various chemical linkages.
Starting from L-tyrosine (Tyr) and its metabolites desaminotyrosine (Dat) and tyramine (Tym), four structurally related model dipeptides were prepared: Dat-Tym (neither N- or C-terminus present), Z-Tyr-Tym (N-terminus protected by benzyloxycarbonyl), Dat-Tyr-Hex (C-terminus protected by a hexyl ester group), and Z-Tyr-Tyr-Hex (both N- and C-termini present, protected by benzyloxycarbonyl and hexyl ester, respectively). The model dipeptides were used as monomers in the synthesis of polycarbonates. The polymerization reaction in the presence of either phosgene or triphosgene proceeded via the phenolic hydroxyl groups. Polymers with molecular weights of 105,000-400,000 da (by gel permeation chromatography, relative to polystyrene standards) were obtained. The physicomechanical properties (solubility, mechanical strength, glass transition and decomposition temperature, processibility) of the polymers were determined, and an attempt was made to correlate the polymer properties with the nature of the N- and C-terminus protecting groups. The presence of the urethane bond at the N-terminus protecting group was found to reduce solubility, ductility, and processibility, probably due to interchain hydrogen bonding. The presence of a C-terminus alkyl ester group increased solubility and processibility. Thus, the most promising candidate polymer for biomedical applications was obtained from Dat-Tyr-Hex, the monomer carrying a C-terminus protecting group only. Since very similar results had recently been obtained for a series of structurally related polyiminocarbonates, the structure property correlations seem to be generally valid.
Samples of high-molecular-weight poly(L-lactide) (PLLA) (Mv = 9.0 x 10(5), a biomaterial developed for plates and screws used in internal fixation of jaw fractures, were implanted subcutaneously in the backs of rats to study tissue reaction to PLLA and to follow the degradation process. The PLLA seemed to follow the degradation pattern typical of biodegradable polyesters. After pure hydrolysis up to about 104 wk, phagocytic activity of macrophages was found at about 143 wk. Full resorption of PLLA was not demonstrated in this study. Except for the early and final parts of the implant period, no acute or chronic inflammatory reaction was observed. No implant was rejected. It is estimated that more than 3 yr will be required for total resorption of PLLA. For bone-healing this long period is of no practical importance. There is no need for removal of PLLA after fracture healing as is the case with metal fixation devices. Thus, PLLA has potential application in internal fixation of fractures and osteotomies in the maxillofacial region and other fractures that are not too heavily loaded in the human body.
Glass-ceramic A-W, containing crystalline apatite and wollastonite in a MgO-CaO-SiO2 glassy matrix shows high bioactivity as well as high mechanical strength, but other ceramics containing the same kinds of crystalline phases in different glassy matrices do not show the same bioactivity. In order to investigate the bone-bonding mechanism of this type of glass-ceramic, surface structural changes of the glass-ceramics after exposure to simulated body fluid were analyzed with various techniques. A solution with ion concentrations which are almost equal to those of the human blood plasma was used as the simulated body fluid, instead of Tris-buffer solution hitherto used. For analyzing the surface structural changes, thin-film x-ray diffraction was used in addition to conventional techniques. It was found that a bioactive glass-ceramic forms a Ca, P-rich layer on its surface in the fluid but nonbioactive ones do not, and that the Ca, P-rich layer consists of carbonate-containing hydroxyapatite of small crystallites and/or defective structure. These findings were common to those of Bioglass-type glasses. So, we conclude that the essential condition for glass and glass-ceramic to bond to bone is the formation of the surface apatite layer in the body environment but it is not essential to contain apatite within the material. Bioactivity of glass and glass-ceramic can be evaluated in vitro by examining the formation of the surface apatite layer in the simulated body fluid described above.
Poly(L-lactide) (PLLA) with an extremely high molecular weight (Mv up to 1 X 10(6)) was synthesized at a low catalyst concentration (0.015 wt%) and temperatures between 100-110 degrees C. Besides good mechanical properties the as-polymerized PLLA exhibited a microporous structure. Plates and screws of this material were used for the treatment of mandibular fractures, both in dogs and in sheep. Bone healing was uneventful and proceeded without callus formation or signs of inflammation. Fracture healing was accompanied by a progressive degradation of the microporous implants of PLLA.
A group of 12 materials was evaluated for tissue compatibility via a sequential histopathologic evaluation of the rabit muscle response to the implanted materials. Tissue samples were obtained daily for 7 days and weekly for 12 weeks to follow the time course of the response. Some cytotoxic samples revealed a rapid and marked response of relatively short duration, whereas others tended to produce a sustained or a long-term, intermittent inflammatory and/or necrotic response. These effects also demonstrated the suitability of 7 days as a satisfactory time period for routine evaluation of rabbit muscle reaction to implanted materials. The histopathologic evaluation of the response was compared with a gross evaluation of the implant site and an independent test of the material by tissue culture (agar–overlay method).
To evaluate the biocompatibility of in vitro predegraded as polymerized poly(L-lactide) (PLLA), a cage implant system was used to investigate white cell and enzyme concentrations with time. The use of a cage permits in a serial fashion a quantitative and qualitative measurement of exudate components formed around an implant. Subcutaneously in rats, caped cages manufactured from stainless-steel mesh were implanted with in vitro predegraded, as-polymerized PLLA, as-polymerized PLLA cylinders, and empty cages serving as controls. In vitro predegradation was used to simulate the degradation products of long-term in vitro degradation. Predegraded PLLA particles were obtained by in vitro hydrolysis at elevated temperatures. The first 7 days of implantation were characterized by an acute inflammatory reaction; the exudate extracted from the cages showed predominantly neutrophils for all types of implants. After day 7, there was a more chronic inflammatory reaction with predominantly macrophages and lymphocytes. There were no significant differences in the total leukocyte concentration or macrophage concentration for any of the cages in the period from 10-21 days. Extracellular enzyme activity also did not show any significant differences among the three types of cages. A possible explanation for the absence of any significant differences could be that the in vitro predegraded particles were sieved before implantation, thus eliminating all small particles (< 70 microns) that are probably mandatory to provoke an increased cellular reaction.
The degradation of high molecular weight as-polymerized poly(L-lactide) (PLLA) is very slow; it takes more than 5.6 yr for total resorption. Moreover, the degradation products of as-polymerized PLLA bone plates, consisting of numerous stable particles of high crystallinity, are related with a subcutaneous swelling in patients 3 yr postoperatively. In order to avoid these complications, polymers were developed that are anticipated to have comparable mechanical properties but a higher degradation rate and do not degrade into highly stable particles that can induce a subcutaneous swelling. On chemical grounds it can be expected that copolymerization of PLLA with 4% D-lactide (PLA96) or by modifying PLLA through cross-linking (CL-PLLA) will lead to less stable particles and a higher degradation rate. To evaluate the long-term suitability of these as-polymerized polymers, the biocompatibility of the degradation products should be studied. Considering the very slow degradation rate of as-polymerized PLLA, in vitro pre-degradation at elevated temperatures was used to shorten the in vivo follow-up periods. In this study, the biocompatibility and degradation of as-polymerized PLLA, PLA96 and CL-PLLA were investigated by implanting pre-degraded particulate materials subcutaneously in rats. Animals were killed after a postoperative period varying from 3 to 80 wk. Light and electron microscopical analysis and quantitative measurements were performed. The histological response of all three pre-degraded materials showed a good similarity with in vivo implanted material. Pre-degraded PLLA induced a mild foreign body reaction and showed a slow degradation rate.(ABSTRACT TRUNCATED AT 250 WORDS)
A series of four polycarbonates derived from the ethyl, butyl, hexyl, and octyl esters of desaminotyrosyl-tyrosine was prepared by condensation polymerization. The resulting polymers had weight average molecular weights ranging from 120,000-450,000, and their chemical structure was confirmed by elemental analysis, nuclear magnetic resonance, and Fourier transform infrared spectroscopy. The polycarbonates were evaluated as degradable biomaterials. Their surface properties were determined by electron spectroscopy for chemical analysis, attenuated total reflectance-Fourier transformed infrared spectroscopy, and contact angle measurement. The degree of surface hydrophobicity was related to the length of the alkyl ester pendent chain. The tensile properties were dependent on the chemical structure of the polymers: For thin, solvent cast film specimens, the tensile modulus varied from 1.2-1.6 GPa, and the strength at break from 60-220 MPa. The degradation of polymeric films was followed in vitro by measuring changes in mechanical strength for up to 40 weeks, and the decrease in molecular weight and changes in surface chemistry for up to 80 weeks. The length of the pendent chain affected the degradation behavior and strength retention; the polymers with short pendent chains were more readily hydrolyzable. For sterilization, ethylene oxide treatment was less destructive, as judged by molecular weight retention, than gamma-irradiation. Spin-cast films of all tested polycarbonates were not cytotoxic toward cultured rat lung fibroblasts. The cell response was influenced by the chemical structure of the polymer. The least hydrophobic polycarbonate (having a short ethyl ester pendent chain) was a more stimulating substrate for cell growth than the more hydrophobic polymers (carrying longer alkyl ester pendent chains).
The effect of 0.1 and 0.5% L- and D-monomers on cultured fibroblasts was determined by studying the proliferation, morphology and cellular activity. The addition of 0.5% monomer reduced the metabolic activity of the cells by about 40%, but the proliferation and morphology were only negatively affected for the 0.5% monomer in combination with an increased osmolarity of the medium. The addition of sucrose, however, resulted in an increased proliferation and acid phosphatase activity, as well as an altered morphology. Therefore, it can be concluded from this study that the osmolarity, as well as the nature and concentration of the added material, can exert an influence on proliferation, morphology and/or cellular activity.
An adequate histologic evaluation is a prerequisite for a good understanding of the behavior of tissue to implant materials. However, despite improvements in histologic sectioning techniques, few studies have used histomorphometric methods for the quantification of the tissue response. This paper discusses new simple histologic grading scales, which can be used for the fast standardized light microscopic analysis of the biocompatibility of hard and soft tissue implants. Two examples of the application of the grading scales are demonstrated.
Five structurally related, aliphatic polyarylates were synthesized from tyrosine-derived diphenols and diacids. The diphenols were a homologous series of three desaminotyrosyl-tyrosine alkyl esters (ethyl, hexyl, octyl) which had previously been used in the synthesis of mechanically strong and tissue-compatible polycarbonates. The diacids (succinic acid, adipic acid, sebacic acid) were selected among compounds that were known to be of low systemic toxicity. By using different diacids as comonomers, the flexibility of the polymer backbone could be varied while the desaminotyrosyl-tyrosine alkyl esters provided pendent chains of various length. Some of the thermal and mechanical properties of the five polymers could be correlated to their chemical structure: the glass transition temperature decreased from 53 to 13 degrees C, and the tensile modulus (measured at room temperature) decreased from 1500 to about 3 MPa when the length of the aliphatic diacid in the polymer backbone and/or the length of the alkyl ester pendent chain was increased. The presence of an arylate bond in the polymer backbone introduced a hydrolytically labile linkage into the polymer structure. Under physiological conditions in vitro all polymers degraded: thin films retained only about 30-40% of their initial molecular weight (Mw) after 26 weeks of storage in phosphate buffer solutions (pH 7.4) at 37 degrees C. Release studies with p-nitroaniline as a model drug indicated that a diffusion controlled release process occurred. The rate of p-nitroaniline release could be correlated with the glass transition temperature of the polymer.
The tissue response and in vivo molecular stability of injection-molded polyhydroxyacids—polylactides (PLA), poly(3-hydroxybutyrate) (PHB), and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHB/VA, 5–22% VA content)—were studied. Polymers were implanted subcutaneously in mice and extirpated at 1, 3, and 6 month in order to study tissue response and polymer degradation.
All polymers were well tolerated by the tissue. No acute inflammation, abscess formation, or tissue necrosis was observed in tissues adjacent to the implanted materials. Furthermore, no tissue reactivity or cellular mobilization was evident remote from the implant site. Mononuclear macrophages, proliferating fibroblasts, and mature vascularized fibrous capsules were typical of the tissue response. Degradation of the polymers was accompanied by an increase in collagen deposition. For the polylactide series, the inflammatory response after 1 month of implantation was less for materials containing the D-unit in the polymer chain, whereas in the case of the polyhydroxybutyrate/valerates, the number of inflammatory cells increased with increasing content of the valerate unit in the polymer chain. Between 1–3 months, there was slightly more tissue response to the PHB and PHB/VA polymers than to PLA. This response is attributed to the presence of leachable impurities and a low molecular weight soluble component in the polyhydroxybutyrate/valerates. At 6 months, the extent of tissue reaction was similar for both types of polymers.
All polylactides degraded significantly (56–99%) by 6 months. For a poly(L-lactide) series, degradation rate in vivo decreased with increasing initial molecular weight of the injection-molded polymer. Several samples showed pronounced bimodal molecular weight distributions (MWD), which may be due to differences in degradation rate, resulting from variability in distribution of crystalline and amorphous regions within the samples. This may also be the result of two different mechanisms, i.e., nonenzymatic and enzymatic, which are involved in the degradation process, the latter being more extensive at the later stage of partially hydrolyzed polymer. The PHB and PHB/VA polymers degraded less (15–43%) than the polylactides following 6 months of implantation. Generally, the polymer with higher valerate content (19%, 22% degraded most. The decrease in molecular weight was accompanied by a narrowing of the MWD for PHB and copolymers; there was no evidence of a bimodal MWD, possibly indicating that the critical molecular weight that would permit enzyme/polymer interaction had not been reached. Weight loss during implantation ranged from 0–50% for the polylactides, whereas for the PHB polymers weight loss ranged from 0–1.6%.
Three poly(L-lactides) with different molecular weights were synthesized. Small blocks (3 x 3 x 2 mm) and rods (25 x 3 x 2 mm) were produced either by injection moulding (amorphous parts, Mvis 200,000 and 120,000, respectively) or machined out of a solid aspolymerized polylactide block (crystalline parts, Mvis 429,000) and implanted into the dorsal muscle of rats. After 1 to 116 wk the rats were killed and the implants were recovered. Histological preparation was carried out using the cutting-grinding technique. All three polylactides had incorporated well, forming a collagenous fibrous layer. Crystalline block polylactide remained stable in form and structure over the whole observation period. Amorphous injection-moulded specimens developed a rough surface within weeks, then deep resorptive lacunae after ca. 1 yr and became totally degraded (Mvis 120,000) or nearly totally degraded (Mvis 200,000) after 2 yr. This velocity of biodegradation seems to meet the requirements for an absorbable material for osteosynthesis. Long-term implantation into rodents brings the problem of foreign-body tumorigenesis independent of the chemical nature of implants (the Oppenheimer effect). Observations in this study and in the literature are discussed.
Since the introduction of polycolide, poly(L-lactide) and their composites as materials for the internal fixation for fractures in humans they have been increasingly used clinically. Here we report the results 2 years after transcortical implantation of poly (L-lactide) and hydroxylapatite containing plugs in the femora of one goat. Special interest was focused on the histologic evaluation of the efferent lymph nodes.
The polymerization of desaminotyrosinetyrosylhexyl ester (DTH) with phosgene gives rise to poly(DTH carbonate), a new pseudopoly(amino acid). To evaluate the performance of this bioabsorbable material in orthopedic applications, the tissue responses elicited by compression-molded pins of poly(DTH carbonate) and clinically used polydioxanone pins (PDS; Orthosorb) were compared. The two types of pins were implanted in the paravertebral muscle and in the metaphyseal proximal tibia and distal femur of 10 White New Zealand Rabbits for 1, 2, 4, and 26 weeks. The tissue response was evaluated using histologic staining of soft- and hard-tissue sections, fluorescent bone marker of incorporation, and backscattered electron imaging. In soft tissue, both poly(DTH carbonate) and PDS elicited a mild inflammatory response resulting in encapsulation. During the disintegration phase, the PDS implants triggered a foreign body response involving the phagocytosis of polymeric debris by histiocytes and giant cells. No such response was observed for poly(DTH carbonate). In hard tissue, close bone apposition was observed throughout the 26-week test period for poly(DTH carbonate) implants. At the 26-week time point, the poly(DTH carbonate) implants exhibited surface erosion and were penetrated by new bone. In contrast, an intervening fibrous tissue layer was always present between the PDS pins and the bone. At 26 weeks, the PDS implants had partially resorbed and a foreign body response characterized by infiltration in several of the implantation sites. This study indicates that poly(DTH carbonate) and PDS exhibit fundamentally different interactions with hard tissue, and that poly(DTH carbonate) is a promising orthopedic implant material.
This is a review of salient studies of sterilization, toxicity, biocompatibility, clinical applications and current work in the field of orthopaedics, using implants made of polylactic acid (PLA), polyglycolic acid (PGA) and their copolymers. The intrinsic nature of these biomaterials renders them suitable for applications where temporally slow releases of bioactive agents in situ may be required. They are also desirable as fixation devices of bone, because they can virtually eliminate osteopenia associated with stress shielding or additional surgery. The majority of currently available sterilization techniques are not suitable for these thermoplastic materials and it may be desirable to develop new sterilization standards, which can account for the special character of PLA-PGA materials. Biocompatibility and toxicity studies suggest that, overall, PLA-PGA biomaterials may be suitable for orthopaedic applications, although certain problems, especially pertaining to reduction in cell proliferation, have been reported. Clinical applications are also promising, albeit not without problems usually associated with transient tissue inflammation. The future of these materials appears bright, especially in soft tissues. They may be used to address the exceedingly complex problem of osteochondral repair, but also as a means to enhance fixation and repair processes in tendons and ligaments.
Evaluation of tyrosine-derived pseudo-poly(amino acids): In vitro cell inter-actions
- J Zhou
- S I Ertel
- H M Buettner
- J Kohn
J. Zhou, S. I. Ertel, H. M. Buettner, and J. Kohn, ''Evaluation of tyrosine-derived pseudo-poly(amino acids): In vitro cell inter-actions,'' in 20th Annual Meeting of the Society for Biomaterials, Boston, Massachusetts, 1994, p. 371.
In vivo comparative study of tyrosine-derived polycarbonates and poly(L-lactic acid)
- K S James
- M C Zimmerman
- J R Parsons
- J Kohn
K. S. James, M. C. Zimmerman, J. R. Parsons, and J. Kohn, ''In vivo comparative study of tyrosine-derived polycarbonates and poly(L-lactic acid),'' in 23rd Annual Meeting of the Society for Biomaterials, New Orleans, 1997, p. 120.