Implantable Drug Delivery Systems and Foreign Body Reaction: Traversing the Current Clinical Landscape

Precise delivery of therapeutics to the target structures is essential for treatment efficiency and safety. Drug administration via conventional routes requires overcoming multiple transport barriers to achieve and maintain the local drug concentration and commonly results in unwanted off-target effects. Patients’ compliance with the treatment schedule remains another challenge. Implantable drug delivery systems (IDDSs) provide a way to solve these problems. IDDSs are bioengineering devices surgically placed inside the patient’s tissues to avoid first-pass metabolism and reduce the systemic toxicity of the drug by eluting the therapeutic payload in the vicinity of the target tissues. IDDSs present an impressive example of successful translation of the research and engineering findings to the patient’s bedside. It is envisaged that the IDDS technologies will grow exponentially in the coming years. However, to pave the way for this progress, it is essential to learn lessons from the past and present of IDDSs clinical applications. The efficiency and safety of the drug-eluting implants depend on the interactions between the device and the hosting tissues. In this review, we address this need and analyze the clinical landscape of the FDA-approved IDDSs applications in the context of the foreign body reaction, a key aspect of implant–tissue integration.

The Granule Size Mediates the In Vivo Foreign Body Response and the Integration Behavior of Bone Substitutes

The physicochemical properties of synthetically produced bone substitute materials (BSM) have a major impact on biocompatibility. This affects bony tissue integration, osteoconduction, as well as the degradation pattern and the correlated inflammatory tissue responses including macrophages and multinucleated giant cells (MNGCs). Thus, influencing factors such as size, special surface morphologies, porosity, and interconnectivity have been the subject of extensive research. In the present publication, the influence of the granule size of three identically manufactured bone substitute granules based on the technology of hydroxyapatite (HA)-forming calcium phosphate cements were investigated, which includes the inflammatory response in the surrounding tissue and especially the induction of MNGCs (as a parameter of the material degradation). For the in vivo study, granules of three different size ranges (small = 0.355–0.5 mm; medium = 0.5–1 mm; big = 1–2 mm) were implanted in the subcutaneous connective tissue of 45 male BALB/c mice. At 10, 30, and 60 days post implantationem, the materials were explanted and histologically processed. The defect areas were initially examined histopathologically. Furthermore, pro- and anti-inflammatory macrophages were quantified histomorphometrically after their immunohistochemical detection. The number of MNGCs was quantified as well using a histomorphometrical approach. The results showed a granule size-dependent integration behavior. The surrounding granulation tissue has passivated in the groups of the two bigger granules at 60 days post implantationem including a fibrotic encapsulation, while a granulation tissue was still present in the group of the small granules indicating an ongoing cell-based degradation process. The histomorphometrical analysis showed that the number of proinflammatory macrophages was significantly increased in the small granules at 60 days post implantationem. Similarly, a significant increase of MNGCs was detected in this group at 30 and 60 days post implantationem. Based on these data, it can be concluded that the integration and/or degradation behavior of synthetic bone substitutes can be influenced by granule size.

Bletilla striata polysaccharide cryogel scaffold for spatial control of foreign-body reaction

Background Implantation of a biomaterial may induce the foreign-body reaction to the host tissue that determines the outcome of the integration and the biological performance of the implants. The foreign-body reaction can be modulated by control of the material properties of the implants. Methods First, we synthesized methacrylated Bletilla striata Polysaccharide (BSP-MA) and constructed a series of open porous cryogels utilizing this material via the freezing-thawing treatment of solvent-precursors systems. Second, Pore size and modulus were measured to characterize the properties of BSP cryogels. Live/dead staining of cells and CCK-8 were performed to test the cytocompatibility of the scaffolds. In addition, the Real-Time qPCR experiments were carried for the tests. Finally, the BSP scaffolds were implanted subcutaneously to verify the foreign-body reaction between host tissue and materials. Results Our data demonstrated that cryogels with different pore sizes and modulus can be fabricated by just adjusting the concentration. Besides, the cryogels showed well cytocompatibility in the in vitro experiments and exhibited upregulated expression levels of pro-inflammation-related genes (Tnfa and Il1b) with the increase of pore size. In vivo experiments further proved that with the increase of pore size, more immune cells infiltrated into the inner zone of materials. The foreign-body reaction and the distribution of immune-regulatory cells could be modulated by tuning the material microstructure. Conclusions Collectively, our findings revealed Bletilla striata polysaccharide cryogel scaffold with different pore sizes can spatially control foreign-body reaction. The microstructure of cryogels could differentially guide the distribution of inflammatory cells, affect the formation of blood vessels and fibrous capsules, which eventually influence the material-tissue integration. This work demonstrates a practical strategy to regulate foreign body reaction and promote the performance of medical devices.

Hematopoietic Stem Cell Gene Therapy for Cystinosis: From Bench-to-Bedside

Cystinosis is an autosomal recessive metabolic disease that belongs to the family of lysosomal storage disorders. The gene involved is the CTNS gene that encodes cystinosin, a seven-transmembrane domain lysosomal protein, which is a proton-driven cystine transporter. Cystinosis is characterized by the lysosomal accumulation of cystine, a dimer of cysteine, in all the cells of the body leading to multi-organ failure, including the failure of the kidney, eye, thyroid, muscle, and pancreas, and eventually causing premature death in early adulthood. The current treatment is the drug cysteamine, which is onerous and expensive, and only delays the progression of the disease. Employing the mouse model of cystinosis, using Ctns−/− mice, we first showed that the transplantation of syngeneic wild-type murine hematopoietic stem and progenitor cells (HSPCs) led to abundant tissue integration of bone marrow-derived cells, a significant decrease in tissue cystine accumulation, and long-term kidney, eye and thyroid preservation. To translate this result to a potential human therapeutic treatment, given the risks of mortality and morbidity associated with allogeneic HSPC transplantation, we developed an autologous transplantation approach of HSPCs modified ex vivo using a self-inactivated lentiviral vector to introduce a functional version of the CTNS cDNA, pCCL-CTNS, and showed its efficacy in Ctns−/− mice. Based on these promising results, we held a pre-IND meeting with the Food and Drug Administration (FDA) to carry out the FDA agreed-upon pharmacological and toxicological studies for our therapeutic candidate, manufacturing development, production of the GMP lentiviral vector, design Phase 1/2 of the clinical trial, and filing of an IND application. Our IND was cleared by the FDA on 19 December 2018, to proceed to the clinical trial using CD34+ HSPCs from the G-CSF/plerixafor-mobilized peripheral blood stem cells of patients with cystinosis, modified by ex vivo transduction using the pCCL-CTNS vector (investigational product name: CTNS-RD-04). The clinical trial evaluated the safety and efficacy of CTNS-RD-04 and takes place at the University of California, San Diego (UCSD) and will include up to six patients affected with cystinosis. Following leukapheresis and cell manufacturing, the subjects undergo myeloablation before HSPC infusion. Patients also undergo comprehensive assessments before and after treatment to evaluate the impact of CTNS-RD-04 on the clinical outcomes and cystine and cystine crystal levels in the blood and tissues for 2 years. If successful, this treatment could be a one-time therapy that may eliminate or reduce renal deterioration as well as the long-term complications associated with cystinosis. In this review, we will describe the long path from bench-to-bedside for autologous HSPC gene therapy used to treat cystinosis.

Bletilla striata Polysaccharide Cryogel Scaffold for Spatial Control of Foreign-body Reaction

BackgroundImplantation of a biomaterial may induce the foreign-body reaction to the host tissue that determines the outcome of the integration and the biological performance of the implant. The level of foreign-body reaction can be modulated by material properties.MethodsFirst, we synthesized methacrylated Bletilla striata Polysaccharide (BSP-MA) and constructed a series of open porous cryogels utilizing this material via the freezing-thawing treatment of solvent-precursors systems. Second, Pore size and rheology were measured to characterize the material properties of cryogels. Live/dead staining of cells and CCK-8 was performed to test the cytocompatibility of the scaffolds. In addition, the Real-Time qPCR experiments were carried for in vitro tests. Finally, the BSP scaffolds were implanted subcutaneously to verify the foreign-body reaction between host tissue and materials.ResultsOur data demonstrated that cryogels with different pore sizes and modulus can be fabricated by just adjusting the concentration. Besides, the cryogels show well cytocompatibility in the in vitro experiments and exhibited upregulated expression levels of pro-inflammation-related genes (Tnfa and Il1b) with the increase of pore size. In vivo experiments further proved that with the increase of pore size, more immune cells infiltrated into the inner zone of materials. The foreign-body reaction and the distribution of immune-regulatory cells could be modulated by tuning the material microstructure.ConclusionsCollectively, our findings revealed Bletilla striata polysaccharide cryogel scaffold with different pore sizes can spatially control foreign-body reaction. The microstructure of cryogels could differentially guide the distribution of inflammatory cells, affect the formation of blood vessels and fibrous capsules, which eventually influence the material-tissue integration. This work demonstrates a practical strategy to regulate foreign body response and promote the performance of medical devices.

Cell-assembled extracellular matrix (CAM): a human biopaper for the biofabrication of pre-vascularized tissues able to connect to the host circulation in vivo

When considering regenerative approaches, the efficient creation of a functional vasculature, that can support the metabolic needs of bioengineered tissues, is essential for their survival after implantation. However, it is widely recognized that the post-implantation microenvironment of the engineered tissues is often hypoxic due to insufficient vascularization, resulting in ischemia injury and necrosis. This is one of the main limitations of current tissue engineering applications aiming at replacing significant tissue volumes. Here, we have explored the use of a new biomaterial, the cell-assembled extracellular matrix (CAM), as a biopaper to biofabricate a vascular system. CAM sheets are a unique, fully biological and fully human material that has already shown stable long-term implantation in humans. We demonstrated, for the first time, the use of this unprocessed human ECM as a microperforated biopaper. Using microvalve dispensing bioprinting, concentrated human endothelial cells (30 millions ml−1) were deposited in a controlled geometry in CAM sheets and cocultured with HSFs. Following multilayer assembly, thick ECM-based constructs fused and supported the survival and maturation of capillary-like structures for up to 26 d of culture. Following 3 weeks of subcutaneous implantation in a mice model, constructs showed limited degradative response and the pre-formed vasculature successfully connected with the host circulatory system to establish active perfusion.This mechanically resilient tissue equivalent has great potential for the creation of more complex implantable tissues, where rapid anastomosis is sine qua non for cell survival and efficient tissue integration.

Influence of Bioinspired Lithium-Doped Titanium Implants on Gingival Fibroblast Bioactivity and Biofilm Adhesion

Soft tissue integration (STI) at the transmucosal level around dental implants is crucial for the long-term success of dental implants. Surface modification of titanium dental implants could be an effective way to enhance peri-implant STI. The present study aimed to investigate the effect of bioinspired lithium (Li)-doped Ti surface on the behaviour of human gingival fibroblasts (HGFs) and oral biofilm in vitro. HGFs were cultured on various Ti surfaces—Li-doped Ti (Li_Ti), NaOH_Ti and micro-rough Ti (Control_Ti)—and were evaluated for viability, adhesion, extracellular matrix protein expression and cytokine secretion. Furthermore, single species bacteria (Staphylococcus aureus) and multi-species oral biofilms from saliva were cultured on each surface and assessed for viability and metabolic activity. The results show that both Li_Ti and NaOH_Ti significantly increased the proliferation of HGFs compared to the control. Fibroblast growth factor-2 (FGF-2) mRNA levels were significantly increased on Li_Ti and NaOH_Ti at day 7. Moreover, Li_Ti upregulated COL-I and fibronectin gene expression compared to the NaOH_Ti. A significant decrease in bacterial metabolic activity was detected for both the Li_Ti and NaOH_Ti surfaces. Together, these results suggest that bioinspired Li-doped Ti promotes HGF bioactivity while suppressing bacterial adhesion and growth. This is of clinical importance regarding STI improvement during the maintenance phase of the dental implant treatment.

New Sintered Porous Scaffolds of Mg,Sr Co-Substituted Hydroxyapatite Support Growth and Differentiation of Primary Human Osteoblasts In Vitro

Strontium (Sr) and Magnesium (Mg) are bioactive ions that have been proven to exert a beneficial effect on bone; therefore, their incorporation into bone substitutes has long been viewed as a possible approach to improve tissue integration. However, the thermal instability of Mg-substituted hydroxyapatites has hitherto limited development. We previously described the creation of thermally consolidated porous constructs of Mg,Sr co-substituted apatites with adequate mechanical properties for their clinical use. The present paper describes the biocompatibility of Mg,Sr co-substituted granules using an alveolar-bone-derived primary model of human osteoblasts. Cells were cultured in the presence of different amounts of hydroxyapatite (HA), Sr-substituted HA, or MgSrHA porous macrogranules (with a size of 400–600 microns, obtained by grinding and sieving the sintered scaffolds) for three and seven days, and their viability was measured by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Protein content was measured using the Lowry assay at the same time points. Cell viability was not impaired by any of the tested compounds. Indirect and direct biocompatibility of these macrogranules was assessed by culturing cells in a previously conditioned medium with HA, SrHA, or MgSrHA, or in the presence of material granules. Osteoblasts formed larger and more numerous nodules around SrHA or MgSrHA granules. Furthermore, cell differentiation was evaluated by alkaline phosphatase staining of primary cells cultured in the presence of HA, SrHA, or MgSrHA granules, confirming the increased osteoconductivity of the doped materials.

Zinc Oxide Nanoparticles Exhibit Favorable Properties to Promote Tissue Integration of Biomaterials

Due to the demographic change, medicine faces a growing demand for tissue engineering solutions and implants. Often, satisfying tissue regeneration is difficult to achieve especially when co-morbidities hamper the healing process. As a novel strategy, we propose the incorporation of zinc oxide nanoparticles (ZnO NPs) into biomaterials to improve tissue regeneration. Due to their wide range of biocompatibility and their antibacterial properties, ZnO NPs are already discussed for different medical applications. As there are versatile possibilities of modifying their form, size, and function, they are becoming increasingly attractive for tissue engineering. In our study, in addition to antibacterial effects of ZnO NPs, we show for the first time that ZnO NPs can foster the metabolic activity of fibroblasts as well as endothelial cells, both cell types being crucial for successful implant integration. With the gelatin sponge method performed on the chicken embryo’s chorioallantoic membrane (CAM), we furthermore confirmed the high biocompatibility of ZnO NPs. In summary, we found ZnO NPs to have very favorable properties for the modification of biomaterials. Here, incorporation of ZnO NPs could help to guide the tissue reaction and promote complication-free healing.