Biological response to chopped-carbon-fiber-reinforced peek.

Polymer composites are being recognized as important implant materials for fracture fixation plates. The use of a composite material is dependent upon the mechanical properties of the material and its biocompatibility. The primary objective of this project was to evaluate 30% chopped-carbon-fiber-reinforced poly(etheretherketone) (CFRPEEK) as a potential material for use as a fracture fixation plate. A two-phase study was conducted. The first phase analyzed the short-term biocompatibility of CFRPEEK through rabbit muscle implant testing. CFRPEEK exhibited a nonspecific foreign body tissue reaction similar to the response observed with ultra-high-molecular-weight polyethylene (UHMWPE). In the second phase, four-hole CFRPEEK plates were implanted as internal fixation devices for transverse midshaft femoral osteotomies in beagles. The plates were effective in promoting fracture healing. A nonspecific foreign body reaction was observed to the plates and to particulate debris.     

Biocompatibility of subcutaneously implanted marine macromolecules cross-linked bio-composite scaffold for cartilage tissue engineering applications

There is an intense interest in developing innovative biomaterials which support the invasion and proliferation of living cells for potential applications in tissue engineering and regenerative medicine. Present study demonstrated the in vivo biocompatibility and toxicity of a macromolecules cross-linked biocomposite scaffold composed of hydroxyapatite, alginate, chitosan and fucoidan abbreviated as HACF. The in vivo biocompatibility and toxicity of HACF scaffold were tested by comparing them with those of a biocompatible surgical metal implant (SMI) in a subcutaneous rat model. Following the implantation, animals were sacrificed and the scaffolds were resected at 1st, 4th, and 8th weeks; the surrounding tissue along with the implant was removed to evaluate its biocompatibility. The effects of implanted biomaterial scaffolds on vital organ systems such as liver, kidney, etc., have been studied by hematology and serum biochemistry. The activities of pro-inflammatory marker enzymes such as COX, 5-LOX, 15-LOX, and NOS were normal in rats implanted with HACF scaffold. Hematological parameters, antioxidant and lipid peroxidation status were also found to be normal in implanted rats same as that of control and SMI. The modulatory effect of implanted scaffold over inflammatory and stress signaling cascades were confirmed by the normalized mRNA expressions of NF-κB, TNF-α and IL-6. The histopathological analysis of liver, kidney and tissue support our results. Taken together, these results demonstrated that HACF biocomposite scaffold signifies its suitability for further research as a scaffold material for cartilage tissue engineering applications.     

A preliminary report on the biocompatibility of photopolymerizable semi-interpenetrating anhydride networks

A new family of poly(anhydrides) (PA) has been developed which can be cured photochemically to produce degradable networks. These degradable anhydride networks may be useful in orthopaedics as bone cements and as matrices for drug delivery. This system, which is a semi-interpenetrating network (semi-IPN), has been evaluated for biocompatibility in subcutaneous tissue in rats and appears to undergo degradation primarily by surface erosion. The inflammatory response to the semi-IPN implants was minimal at both short (3 and 6 weeks) and long (28 weeks) time points and the fibrotic response was largely absent throughout the duration of this study. Furthermore, the OrthoCure implant material integrated well with the surrounding tissue and was invaded with vascularized connective tissue. For reference, linear PA controls were tested and showed a foreign body response culminating in the formation of relatively avascular fibrous capsule several cell layers thick, which became thicker over time, a response similar to what is typically observed in FDA approved implantable polymeric device systems.     

Foreign body reaction to biomaterials

The foreign body reaction composed of macrophages and foreign body giant cells is the end-stage response of the inflammatory and wound healing responses following implantation of a medical device, prosthesis, or biomaterial. A brief, focused overview of events leading to the foreign body reaction is presented. The major focus of this review is on factors that modulate the interaction of macrophages and foreign body giant cells on synthetic surfaces where the chemical, physical, and morphological characteristics of the synthetic surface are considered to play a role in modulating cellular events. These events in the foreign body reaction include protein adsorption, monocyte/macrophage adhesion, macrophage fusion to form foreign body giant cells, consequences of the foreign body response on biomaterials, and cross-talk between macrophages/foreign body giant cells and inflammatory/wound healing cells. Biomaterial surface properties play an important role in modulating the foreign body reaction in the first two to four weeks following implantation of a medical device, even though the foreign body reaction at the tissue/material interface is present for the in vivo lifetime of the medical device. An understanding of the foreign body reaction is important as the foreign body reaction may impact the biocompatibility (safety) of the medical device, prosthesis, or implanted biomaterial and may significantly impact short- and long-term tissue responses with tissue-engineered constructs containing proteins, cells, and other biological components for use in tissue engineering and regenerative medicine. Our perspective has been on the inflammatory and wound healing response to implanted materials, devices, and tissue-engineered constructs. The incorporation of biological components of allogeneic or xenogeneic origin as well as stem cells into tissue-engineered or regenerative approaches opens up a myriad of other challenges. An in depth understanding of how the immune system interacts with these cells and how biomaterials or tissue-engineered constructs influence these interactions may prove pivotal to the safety, biocompatibility, and function of the device or system under consideration.     

Presence of adipose fat as a criterion of implant compatibility.

An analysis of the tissue sections from previous implant studies was performed define additional criteria which could be considered in determinations of biocompatibility of implant materials. Adult albino rabbits were implanted with biomaterials in the sacrospinalis muscle for periods of 2, 6, 18, and 54 weeks. Fourteen different implant materials were used in this study. The tissues were examined histologically for the appearance of adipose fat cells within the membrane surrounding the implant as an important criterion of tissues implant compatibility. The results were compared with other previously used criteria in judging biocompatibility of implant materials. For the most compatible nonreactive materials, adipose tissue formation within the pseudomembrane began at 6 weeks and was quite extensive at 54 weeks. The reactive materials studied by us did not exhibit this phenomenon.     

A review of the biomaterials technologies for infection-resistant surfaces

Anti-infective biomaterials need to be tailored according to the specific clinical application. All their properties have to be tuned to achieve the best anti-infective performance together with safe biocompatibility and appropriate tissue interactions. Innovative technologies are developing new biomaterials and surfaces endowed with anti-infective properties, relying either on antifouling, or bactericidal, or antibiofilm activities. This review aims at thoroughly surveying the numerous classes of antibacterial biomaterials and the underlying strategies behind them. Bacteria repelling and antiadhesive surfaces, materials with intrinsic antibacterial properties, antibacterial coatings, nanostructured materials, and molecules interfering with bacterial biofilm are considered. Among the new strategies, the use of phages or of antisense peptide nucleic acids are discussed, as well as the possibility to modulate the local immune response by active cytokines. Overall, there is a wealth of technical solutions to contrast the establishment of an implant infection. Many of them exhibit a great potential in preclinical models. The lack of well-structured prospective multicenter clinical trials hinders the achievement of conclusive data on the efficacy and comparative performance of anti-infective biomaterials.     

The challenge of integrating devices into the central nervous system

Implanted biomedical devices are playing an increasingly important role in the treatment of central nervous system disorders. While devices such as deep brain stimulation electrodes and drug delivery systems have shown clinical success in chronic applications, other devices such as nerve guidance substrates and recording electrodes that operate over a very short length scale have not had the same kind of clinical impact. By reviewing what is currently known about the brain tissue response to implanted electrodes, the authors propose that the foreign-body response, which changes the tissue structure immediately surrounding implanted devices, may be the reason near-function devices are stalled in preclinical development. The article concludes by reviewing recent efforts to reduce the foreign body response, which shows promise to accelerate the clinical development of this new generation of biomedical devices.     

Characterization of microglial attachment and cytokine release on biomaterials of differing surface chemistry

The clinical usefulness of central nervous system recording electrodes is currently limited by inconsistent long-term performance that is believed to be governed by the brain tissue response to the implant. In this study, we observed persistent macrophage biomarker expression at the biotic-abiotic interface surrounding implanted electrodes over a 12-week indwelling period. Using the cell type-specific marker CD11b to examine the cells attached to electrodes retrieved over the indwelling period, we found that most of the cells were activated microglia, the resident macrophage of brain tissue, indicating that the implanted electrodes behave as a persistent inflammatory stimulus. To determine the potential usefulness of different materials as coatings for implanted electrodes, we examined brain-derived microglial cell attachment and cytokine release on a number of medically relevant materials. Our results suggest that activated microglia attach to many of the materials used as external coatings for electrode manufacture, and likely serve as a source of pro-inflammatory and neurotoxic cytokines that may be responsible for reducing the biocompatibility of such implants. Our results also indicate that low protein-binding coatings may be useful in reducing microglial attachment upon implantation in brain tissue and may provide a means of improving electrode biocompatibility.     

Modulation of the foreign body response to implanted sensor models through device-based delivery of the tyrosine kinase inhibitor,masitinib

The host foreign body response (FBR) adversely effects the performance of numerous implanted biomaterials especially biosensors, including clinically popular glucose-monitoring sensors. Reactive formation of a fibrous capsule around implanted sensors hinders the transport of essential analytes to the sensor from the surrounding tissue, resulting in loss of glucose response sensitivity and eventual sensor failure. Several strategies have sought to mitigate the foreign body response's effects on CGM sensors through the use of local delivery of pharmaceuticals and biomolecules with limited success. This study describes release of a tyrosine kinase inhibitor – masitinib – from the sensor implant to target tissue resident mast cells as key mediators of the FBR. Model implants are coated with a composite polymer hydrophilic matrix that rapidly dissolves upon tissue implantation to deposit slower-degrading polymer microparticles containing masitinib. Matrix dissolution limits coating interference with sensor function while establishing a local controlled-release delivery depot formulation to alter implant tissue pharmacology and addressing the FBR. Drug efficacy was evaluated in a murine subcutaneous pocket implant model. Drug release extends to more than 30 days in vitro. The resulting FBR in vivo, evaluated by implant capsule thickness and inflammatory cell densities at 14, 21, and 28 days, displays statistically significant reduction in capsule thickness around masitinib-releasing implant sites compared to control implant sites.     

Immune response in biocompatibility.

Biocompatibility is concerned with the interactions that occur between biomaterials and host tissues. As foreign objects in that host tissue these materials may initiate several types of response. It has often been postulated that the immune response, by which the host normally defends itself against invasion by foreign organisms, can be involved in the response to biomaterials. This review discusses the mechanisms by which this could occur and the evidence that suggests the immune response is indeed of significance in biocompatibility.     

Polylysine-Modified PEG-Based Hydrogels to Enhance the Neuro–Electrode Interface

Neural prostheses are a promising technology in the treatment of lost neural function. However, poor biocompatibility of these devices inhibits the formation of a robust neuro–electrode interface. Several factors including mechanical mismatch between the device and tissue, inflammation at the implantation site, and possible electrical damage contribute to this response. Many researchers are investigating polymeric brain mimetic coatings as a means to improve integration with nervous tissue. Specifically, hydrogels, constructs also employed in tissue engineering, have been explored because of their structural and mechanical similarity to native tissue. However, many hydrogel materials (e.g., poly(ethylene glycol) (PEG)) do not support cell adhesion. In this work, we report a technique to enhance the interface between polymeric brain mimetic coatings and neural tissue using adhesion molecules. In particular, polylysine-modified PEG-based hydrogels were synthesized, characterized and shown to promote neural adhesion using a PC12 cell line. In addition, we examined adhesion behavior of a PEG-co-polymer and found that these materials adhere to electrodes for at least 4 weeks. These results suggest that polylysine–PEG hydrogel biomaterials are biocompatible and can enhance stability of chronic neural interfaces.     

Biomaterial biocompatibility and the macrophage

The biocompatibility of biomaterials at implant sites is controlled by the tissue/material interaction. A major cell in the tissue reaction is the macrophage. A summary is presented on macrophage mediation of cellular and humoral regulatory pathways in inflammatory and immune responses.     

组织工程相关生物材料与巨噬细胞相互作用研究进展

宿主的炎症反应是组织对损伤和异物的正常应答,炎症的强度和持久性影响生物材料在体内的生物相容性和稳定性.巨噬细胞是调控宿主免疫和炎症反应的重要细胞.因此它对生物材料的响应性在对认知材料-宿主反应中有重要作用.本文综述了组织工程相关生物材料与巨噬细胞相互作用的研究进展.通过设计材料的物理化学结构和表面特性,可以调控巨噬细胞在材料表面的黏附、激活、融合、凋亡等行为以及材料在动物体内引发的宿主反应,从而提高生物材料的生物相容性.     

Evaluation of host inflammatory responses of β-tricalcium phosphate bioceramics caused by calcium pyrophosphate impurity using a subcutaneous model

Implantation of synthetic materials into body elicits inflammatory host responses that limit medical device integration and biological performance. Since the effective use of biomaterials in vivo requires good biocompatibility and bio-functionality, it is vital that we assess the inflammatory reactions provoked by various implanted biomaterials. In chemical precipitation of β-tricalcium phosphate [β-Ca?(PO?)?, β-TCP], the impurity of calcium pyrophosphate (Ca?P?O?, CPP) will easily appear if the preparation conditions are not well controlled. To test the influences of CCP-impurity on the biocompatibility of the material, four groups of β-TCP ceramic samples doped with 0.5-10 wt % of CCP impurity, and pure β-TCP and CCP samples were fabricated and implanted in rat subcutaneous site for one, two, and four weeks. The host tissue responses to the ceramics were evaluated by histomorphometric analysis, and the results were compared with pure β-TCPbioceramics. The results show that the CPP impurity can elicit and stimulate the inflammatory responses at the tissue/implant interface. Moreover, with the increase of CPP doping amount, the inflammation increases apparently. However, the pure β-TCP bioceramics only present slight post-implantation inflammatory responses. The influence of the CPP doping on the inflammatory responses is mainly related to a microparticles release because of an insufficient sintering of β-TCP by CPP doping. The microparticle release could be at the origin of local inflammation and cell/tissue damages. Therefore, to obtain perfect biocompatibility and high quality β-TCP bioceramics, it is important to avoid and control the CPP impurity in the preparation of β-TCP powders and bioceramics.     

The foreign body response to the Utah Slant Electrode Array in the cat sciatic nerve

As the field of neuroprosthetic research continues to grow, studies describing the foreign body reaction surrounding chronic indwelling electrodes or microelectrode arrays will be critical for assessing biocompatibility. Of particular importance is the reaction surrounding penetrating microelectrodes that are used to stimulate and record from peripheral nerves used for prosthetic control, where such studies on axially penetrating electrodes are limited. Using the Utah Slant Electrode Array and a variety of histological methods, we investigated the foreign body response to the implanted array and its surrounding silicone cuff over long indwelling periods in the cat sciatic nerve. We observed that implanted nerves were associated with increased numbers of activated macrophages at the implant site, as well as distal to the implant, at all time points examined, with the longest observation being 350 days after implantation. We found that implanted cat sciatic nerves undergo a compensatory regenerative response after the initial injury that is accompanied by shifts in nerve fiber composition toward nerve fibers of smaller diameter and evidence of axons growing around microelectrode shafts. Nerve fibers located in fascicles that were not penetrated by the array or were located more than a few hundred microns from the implant appeared normal when examined over the course of a year-long indwelling period.     

Spatiotemporal effects of a controlled-release anti-inflammatory drug on the cellular dynamics of host response

In general, biomaterials induce a non-specific host response when implanted in the body. This reaction has the potential to interfere with the function of the implanted materials. One method for controlling the host response is through local, controlled-release of anti-inflammatory agents. Herein, we investigate the spatial and temporal effects of an anti-inflammatory drug on the cellular dynamics of the innate immune response to subcutaneously implanted poly(lactic-co-glycolic) microparticles. Noninvasive fluorescence imaging was used to investigate the influence of dexamethasone drug loading and release kinetics on the local and systemic inhibition of inflammatory cellular activities. Temporal monitoring of host response showed that inhibition of inflammatory proteases in the early phase was correlated with decreased cellular infiltration in the later phase of the foreign body response. We believe that using controlled-release anti-inflammatory platforms to modulate early cellular dynamics will be useful in reducing the foreign body response to implanted biomaterials and medical devices.     

Evaluation of the biocompatibility of calcium phosphate cement/PLGA microparticle composites

In this study, the biocompatibility of a calcium phosphate (CaP) cement incorporating poly (D,L-lactic-co-glycolic acid) (PLGA) microparticles was evaluated in a subcutaneous implantation model in rats. Short-term biocompatibility was assessed using pure CaP discs and CaP discs incorporating PLGA microparticles (20% w/w) with and without preincubation in water. Long-term biocompatibility was assessed using CaP discs incorporating varying amounts (5, 10, or 20% w/w) and diameter sizes (small, 0-50 mum; medium, 51-100 mum, or large, 101-200 mum) of PLGA microparticles. The short-term biocompatibility results showed a mild tissue response for all implant formulations, irrespective of disc preincubation, during the early implantation periods up to 12 days. Quantitative histological evaluation revealed that the different implant formulations induced the formation of similar fibrous tissue capsules and interfaces. The results concerning long-term biocompatibility showed that all implants were surrounded by a thin connective tissue capsule (<10 layers of fibroblasts). Additionally, no significant differences in capsule and interface scores were observed between the different implant formulations. The implants containing 20% PLGA with medium- and large-sized microparticles showed fibrous tissue ingrowth throughout the implants, indicating PLGA degradation and interconnectivity of the pores. The results demonstrate that CaP/PLGA composites evoke a minimal inflammatory response. The implants containing 20% PLGA with medium- and large-sized microparticles showed fibrous tissue ingrowth after 12- and 24-weeks indicating PLGA degradation and interconnectivity of the pores. Therefore, CaP/PLGA composites can be regarded as biocompatible biomaterials with potential for bone tissue engineering and advantageous possibilities of the microparticles regarding material porosity.     

In vivo magnetic resonance imaging and relaxometry study of a porous hydrogel implanted in the trapezius muscle of rabbits

In vivo magnetic resonance imaging (MRI) and relaxometry were performed to assess noninvasively the tissue reaction and the biological integration of hydrogels made of poly[N-(2-hydroxypropyl) methacrylamide] (PHPMA) after implantation in the trapezius muscle of rabbits. The benefits of incorporating RGD peptide sequences in the polymer backbone were also investigated. The histological status of each implant was probed by the trend of their transversal relaxation times, T(2), while their biocompatibility was evaluated by analyzing the host tissue response through the evolution of the relaxation times of the adjacent muscle tissue. MR results showed the good acceptability of both hydrogels by the host tissue. The transversal relaxation curves of each implant exhibited two distinct phases as a function of implantation time: (1) a monoexponential phase, dominated by the influx of fluids inside the implants; and (2) a biexponential phase related to the infiltration of cells and the granulation tissue formation within the porous structure of each polymer. These MR findings were correlated with the results of conventional histological analyses. The present study demonstrates the effectiveness of MR methods in noninvasively monitoring the biocompatibility and histological status of implanted porous biomaterials.     

Effects of sterilization on implant mechanical property and biocompatibility

This article concisely reviews the effects of sterilization on the mechanical properties and surface chemistries of implantable biomaterials. This article also summarizes the biological effects of the sterilization-related changes in the implant. Because there are so many different types of implant materials currently in use (including metals, polymers, and diverse biological materials), the response of tissue to these different materials varies dramatically. This review further discusses the effects of sterilization on in vivo and in vitro tissue response specifically to implantable metals and polyethylene, with the possibility of future biocompatibility testing of the implants sterilized with supercritical phase carbon dioxide sterilization.