Effect of temperature and ultraviolet light on the bacterial kill effectiveness of antibiotic-infused 3D printed implants.

Drug eluting 3D printed polymeric implants have great potential in orthopaedic applications since they are relatively inexpensive and can be designed to be patient specific thereby providing quality care. Fused Deposition Modeling (FDM) and Stereolithography (SLA) are among the most popular techniques available to print such polymeric implants. These techniques facilitate introducing antibiotics into the material at microscales during the manufacturing stage and subsequently, the printed implants can be engineered to release drugs in a controlled manner. However, FDM uses high temperature to melt the filament as it passes through the nozzle and SLA relies on exposure to nanoscale wavelength ultraviolet (UV) light which can adversely affect the anti-bacterial effectiveness of the antibiotics. The focus of this article is two-fold: i) Examine the effect of high temperature on the bacterial kill-effectiveness of eluted antibiotics through Polycaprolactone (PCL) based femoral implants and ii) Examine the effect of exposure to ultraviolet (UV) light on the bacterial kill-effectiveness of eluted antibiotics through femoral implants made up of a composite resin with various weight fractions of Polyethylene Glycol (PEG) and Polyethylene Glycol Diacrylate (PEGDA). Results indicate that even after exposing doxycycline, vancomycin and cefazolin at different temperatures between 20oC and 230oC, the antibiotics did not lose their effectiveness (kill radius of at least 0.85 cm). For doxycycline infused implants exposed to UV light, it was seen that a resin with 20 % PEGDA and 80 % PEG had the highest efficacy (1.8 cm of kill radius) and the lowest efficacy was found in an implant with 100 % PEGDA (1.2 cm of kill radius).

Efficacy of eluted antibiotics through 3D printed femoral implants.

Costs associated with musculoskeletal diseases in the United States account for 5.7% of the Gross Domestic Product (GDP) (Weinstein et al. 2018). As such, there is a need to pursue new ideas in orthopaedic implants that can decrease cost and improve patient care. In the recent years, 3D printing of polymers using Fused Deposition Modeling (FDM) and metals using Direct Metal Laser Sintering (DMLS) has opened several exciting possibilities to create customized orthopaedic implants. Such implants can be engineered to release antibiotics in a controlled manner by infusing the drug into the material during manufacturing stage. However, the prevalence of high temperature could impact the anti-bacterial effectiveness of the eluted antibiotics in such implants. An alternative approach to circumvent this issue would be to modify the implant geometry to incorporate built-in design features such as micro-channels and reservoirs in which antibiotics can be introduced prior to the surgical procedure. Irrespective of the approach used, the ability of 3D printed orthopaedic implants to elute antibiotics, and the rate of elution are not well understood. The purpose of this article is to study the elution of doxycycline through 3D printed femoral implants using three different materials: Poly-Lactic Acid (PLA), Poly-Caprolactone (PCL) and Titanium grade Ti-6Al-4V. The PLA and Ti-6Al-4V implants were designed with built-in reservoirs and micro-channels in which doxycycline was introduced post the manufacturing stage. However, the PCL implants were printed from a PCL spool that was infused with doxycycline using an extruder. The PLA and Ti-6Al-4V experiments were run for a period of 31 days and the PCL experiment for one day. The antibacterial ability of eluted doxycycline from all implants were examined using Kirby-Bauer test on the bacteria E.coli k-12. The results show that most of doxycycline eluted through the three materials in the first 24 hours. After the initial spike, a steady release was achieved for the PLA and Ti-6Al-4V implants for 30 days. During this timeframe, Ti-6Al-4V implants released more doxycycline than the PLA implant. The eluted antibiotics through all the implants demonstrated the ability to kill bacteria in the subsequent Kirby-Bauer test. These outcomes show that irrespective of how the antibiotics were introduced, 3D printed polymeric and metallic implants have great potential in orthopaedic applications.

Design maps for scaffold constructs in bone regeneration.

In this article, we propose a methodology for the rational design of scaffold constructs in bone-tissue engineering. The construct under investigation is a sandwich structure with an Intramedullary rod (IM), a Biological Sponge (BS) and an External sleeve (ES). The IM rod provides axial resistance, BS facilitates the growth of new bone and ES provides stability to the construct by resisting torsion and bending. We demonstrate that only select combinations of stiffness between IM and ES facilitate the growth of new bone. Perren's interfragmentary strain theory is employed to clearly identify regions favoring bone growth from those favoring the formation of cartilage. Finally, design maps are constructed that clearly identify the combinations facilitating timely bone growth.

Enabling individualized therapy through nanotechnology.

Individualized medicine is the healthcare strategy that rebukes the idiomatic dogma of 'losing sight of the forest for the trees'. We are entering a new era of healthcare where it is no longer acceptable to develop and market a drug that is effective for only 80% of the patient population. The emergence of "-omic" technologies (e.g. genomics, transcriptomics, proteomics, metabolomics) and advances in systems biology are magnifying the deficiencies of standardized therapy, which often provide little treatment latitude for accommodating patient physiologic idiosyncrasies. A personalized approach to medicine is not a novel concept. Ever since the scientific community began unraveling the mysteries of the genome, the promise of discarding generic treatment regimens in favor of patient-specific therapies became more feasible and realistic. One of the major scientific impediments of this movement towards personalized medicine has been the need for technological enablement. Nanotechnology is projected to play a critical role in patient-specific therapy; however, this transition will depend heavily upon the evolutionary development of a systems biology approach to clinical medicine based upon "-omic" technology analysis and integration. This manuscript provides a forward looking assessment of the promise of nanomedicine as it pertains to individualized medicine and establishes a technology "snapshot" of the current state of nano-based products over a vast array of clinical indications and range of patient specificity. Other issues such as market driven hurdles and regulatory compliance reform are anticipated to "self-correct" in accordance to scientific advancement and healthcare demand. These peripheral, non-scientific concerns are not addressed at length in this manuscript; however they do exist, and their impact to the paradigm shifting healthcare transformation towards individualized medicine will be critical for its success.

3D printed liner for treatment of periprosthetic joint infections.

In the United States, long standing deep infections of joint arthroplasty, such as total knee and total hip replacements, are treated with two-stage exchange. This requires the removal of the prior implant, placement of an antibiotic eluting spacer block made of polymethylmethacrylate (PMMA), followed by re-implantation of a new implant after treatment with intravenous antibiotics for six to eight weeks. Unfortunately, the use of PMMA as a spacer material has limitations in terms of mechanical and drug-eluting properties. PMMA is brittle and elutes most of the antibiotics within the first few days. Furthermore, the polymerization reaction for PMMA is highly exothermic, thereby limiting the use to heat-stable antibiotics. We hypothesize that the use of a 3D printed polymeric liner made of polylactic acid (PLA) would overcome the limitations of PMMA because it is a stronger and a less brittle material than PMMA. Furthermore, the liner can also act as a controlled drug delivery vehicle by using built in reservoirs and a network of micro-channels as well as by incorporating antibiotics directly into the polymer during manufacturing stage. Finally, the liner can be 3D printed according to the anatomy of the patient and thereby has the potential to transform the manner in which periprosthetic joint infections are currently treated.

Shaping the micromechanical behavior of multi-phase composites for bone tissue engineering.

Mechanical stiffness is a fundamental parameter in the rational design of composites for bone tissue engineering in that it affects both the mechanical stability and the osteo-regeneration process at the fracture site. A mathematical model is presented for predicting the effective Young's modulus (E) and shear modulus (G) of a multi-phase biocomposite as a function of the geometry, material properties and volume concentration of each individual phase. It is demonstrated that the shape of the reinforcing particles may dramatically affect the mechanical stiffness: E and G can be maximized by employing particles with large geometrical anisotropy, such as thin platelet-like or long fibrillar-like particles. For a porous poly(propylene fumarate) (60% porosity) scaffold reinforced with silicon particles (10% volume concentration) the Young's (shear) modulus could be increased by more than 10 times by just using thin platelet-like as opposed to classical spherical particles, achieving an effective modulus E approximately 8 GPa (G approximately 3.5 GPa). The mathematical model proposed provides results in good agreement with several experimental test cases and could help in identifying the proper formulation of bone scaffolds, reducing the development time and guiding the experimental testing.

Universal elastic anisotropy index.

Practically all elastic single crystals are anisotropic, which calls for an appropriate universal measure to quantify the extent of anisotropy. A review of the existing anisotropy measures in the literature leads to a conclusion that they lack universality in the sense that they are non-unique and ignore contributions from the bulk part of the elastic stiffness (or compliance) tensor. Proceeding from extremal principles of elasticity, we introduce a new universal anisotropy index that overcomes the above limitations. Furthermore, we establish special relationships between the proposed anisotropy index and the existing anisotropy measures for special cases. A new elastic anisotropy diagram is constructed for over 100 different crystals (from cubic through triclinic), demonstrating that the proposed anisotropy measure is applicable to all types of elastic single crystals, and thus fills an important void in the existing literature.