High-strength, 3D-printed Antibiotic-eluting Spacer to treat Periprosthetic Joint Infection

Total joint arthroplasty (TJA) is the replacement of damaged or arthritic joints with synthetic components to improve patient mobility and quality of life. It is a highly effective procedure with a low rate of complications. However, due to the sheer volume of TJA operations, which is over a million per year in the U.S., there are tens of thousands of patients who experience severe complications, such as mechanical loosening, periprosthetic fracture, implant failure, and periprosthetic joint infection (PJI). Perhaps the most severe is PJI, which is an infection of the tissue surrounding the implant, generally as a result of a pathogen, primarily Staphylococcus aureus (S. aureus), entering the joint through the open wound during the surgical procedure. Although the immune system can usually eliminate invading pathogens effectively, the presence of a foreign body, in this case a synthetic joint, significantly reduces the concentration of bacteria required to induce infection due to the ability of bacteria to attach and grow on the surface of the implant. Over time this leads to pain, redness, swelling, and weakening of the joint that could necessitate amputation if untreated.The gold standard treatment for PJI is a two-stage exchange. In the first stage, the infected device is removed, and the infected tissue is debrided and irrigated to eliminate as much of the infection as possible. Then, a new device, called a spacer, is implanted into the joint in place of the original prosthetic. A spacer is an articulating device composed of poly(methyl methacrylate) (PMMA), commonly called bone cement, that releases antibiotics long-term to treat any remaining infected tissue. The advantage of PMMA over possible alternative biomaterials is 1) the ability to mix antibiotics into the cement before molding it into a desired shape, 2) a porous structure that enables antibiotics to leach from the matrix, and 3) sufficient mechanical strength to support partial load-bearing activity during the treatment period. Currently, the FDA has only approved pre-formed spacers with gentamicin, which limits them from treating bacteria that are resistant to gentamicin. While there used to be a mold available for surgeons to form PMMA spacers in the operating room with antibiotics of their choosing, that mold has since been recalled by the FDA. The spacer requires 6-12 weeks of antibiotic elution to eliminate the infection. After the surgeon determines the infection is gone, the second stage is the removal of the spacer and replacement with new sterile prosthetic components. The second stage is necessary since PMMA is too weak to support long-term full load-bearing activity, so the spacer must be replaced with stronger metal components to make sure the implant does not break, which could lead to serious consequences for the patient. The weak mechanical properties are a significant limitation of PMMA during the 6-12 week treatment period because the spacer frequently breaks when patients do not use ambulatory assist devices to facilitate mobility. A broken spacer can lead to soft tissue and bone damage and requires an additional surgery to replace the spacer. Several surgeries can be painful for the patient and extremely costly to the healthcare system. An ideal alternative spacer would have greater mechanical strength to reduce mechanical complications and the number of surgeries needed to treat PJI. In addition to poor mechanical properties, a second limitation of PMMA spacers is an inadequate antibiotic release profile to treat PJI. Since PMMA is non-biodegradable, antibiotics mixed throughout the cement cannot easily escape from the matrix to elute into the surrounding tissue. In fact, only antibiotics close to the implant surface are able to escape. This causes a burst release of antibiotics in the first few days of implantation with sub-therapeutic release thereafter. This can not only lead to persistence of the infection but can also induce antibiotic resistance, making it more challenging to treat the infection. Furthermore, PMMA cement sets with an exothermic reaction that is incompatible with many antibiotics. Currently only certain antibiotics can maintain their therapeutic efficacy following the exothermic reaction. Overall, PMMA spacers are an ineffective treatment for PJI due to poor mechanical properties and antibiotic release. An ideal alternative device would have greater mechanical strength and long-term release of therapeutic levels of antibiotics to effectively eliminate an infection. In this dissertation, I propose a novel spacer that can more effectively treat PJI vs. PMMA spacers due to the ability to modulate its antibiotic release to a desired profile, increase its mechanical strength tantamount to primary prosthetic components used in TJA, and minimize the ability of bacteria to attach and grow on its surface. The proposed technology takes advantage of the rapidly growing technology of additive manufacturing, also known as 3D-printing, which enables the manufacture of devices with complex structures. I propose 3D-printing joint devices with an internal reservoir to be loaded with a biodegradable carrier that releases antibiotics through 3D-printed channels that connect the reservoir to the surrounding tissue. While conventional manufacturing methods cannot make an internal reservoir with channels, 3D-printing enables precise control of the reservoir and channel geometry to tune the antibiotic release profile. A major advantage of this design over PMMA is the separation of the biomaterial that provides mechanical strength and the biomaterial that releases the antibiotics. In this way, I can 3D-print the device from a material with greater strength than PMMA, such as cobalt-chrome and titanium alloys, and I can load the reservoir with a biodegradable material that releases therapeutic levels of antibiotics over longer periods of time than PMMA. In chapter 3 of this dissertation, I assess the ability to modulate antibiotic release from 3D-printed reservoirs. I vary the geometry of reservoirs, including channel diameter, length, and quantity, to determine the effect on the in vitro antibiotic release from a carrier, in this case calcium sulfate, which is a biodegradable bioceramic frequently used as a bone void filler. Decreasing channel diameter and increasing channel length extends the release of antibiotics by extending the distance the antibiotics must diffuse through the carrier to reach the surrounding medium. To understand the mechanism of release, I develop a computational model of antibiotic release by simulating the reservoir as a 3D matrix in MATLAB. I model diffusion as a random walk and degradation as a progressive erosion over time. After fitting the diffusion and degradation constants to the data, the model effectively predicts the antibiotic release profile of a large range of reservoir geometries. This simple model can help rapidly prototype devices with a customized antibiotic elution profile to effectively treat PJI. In addition, I tested two carriers, calcium sulfate and tri-calcium phosphate, which degrades more slowly than calcium sulfate. Increasing the ratio of tri-calcium phosphate to calcium sulfate extends the release of antibiotics by decreasing the degradation of the bioceramic. Thus, modifying the properties of the carrier is another method to tuning antibiotic release in addition to reservoir geometry. Lastly, I studied the mechanical properties of 3D-printed reservoirs. Increasing the diameter of the channels decreases the mechanical strength of the reservoirs due to reduced structural support of the 3D-printed material. However, using 3D-printing, I can create lattice structures within the reservoir to provide additional mechanical support while still leaving sufficient volume to load an antibiotic-impregnated carrier. Overall, chapter 3 shows a multitude of methods to flexibly modulate both antibiotic release and mechanical strength to improve the ability to treat PJI vs. PMMA. In chapter 4, I study the ability of bacteria to form biofilm on the surface of different orthopedic materials, including 3D-printed metals that could potentially be used to make reservoirs. Biofilm is a conglomerate of microorganisms, most commonly S. aureus in PJI cases, that forms on the surface of an implant. Biofilm organizes in such a way to provide protection from the host immune system and antibiotics, making biofilm significantly harder to eliminate than planktonic, or free-floating, bacteria. It requires up to a thousand times higher concentration to eliminate bacteria in biofilm vs. planktonic bacteria. Therefore, in addition to high mechanical strength and long-term antibiotic release, another important property of an effective spacer is a reduced affinity for bacteria to form biofilm on the implant surface. I use a CDC biofilm reactor to model the in vivo conditions of PJI to grow bacteria on the surface of numerous relevant biomaterials. Using several quantitative methods, I found that biofilm grows more readily on non-polished 3D-printed metals and plastics, such as PMMA and ultra-high molecular weight polyethylene compared to polished and machined metals. To understand the mechanism, I measured the surface roughness and hydrophobicity of the materials. Materials with greater roughness and hydrophobicity developed more biofilm than smoother, hydrophilic materials. Metals are more hydrophilic and can be polished to a lower surface roughness value than PMMA. The data show that PMMA is not only mechanically weak and has a poor antibiotic release profile but also provides an additional surface for bacteria to readily form biofilm that can potentially worsen the existing infection. Taken together, this dissertation provides a comprehensive study of the advantages of hand-polished 3D-printed metal spacers with antibiotic-eluting reservoirs to effectively treat PJI vs. PMMA spacers due to 1) improved mechanical properties, 2) the ability to modulate antibiotic release to a wide range of release profiles, and 3) a reduced affinity of bacteria to form biofilm on the spacer surface.