Toward Designing of Anti-infective Hydrogels for Orthopedic Implants: From Lab to Clinic

An alarming increase in implant failure incidence due to microbial colonization on the administered orthopedic implants has become a horrifying threat to replacement surgeries and related health concerns. In essence, microbial adhesion and its subsequent biofilm formation, antibiotic resistance, and the host immune system’s deficiency are the main culprits. An advanced class of biomaterials termed anti-infective hydrogel implant coatings are evolving to subdue these complications. On this account, this review provides an insight into the significance of anti-infective hydrogels for preventing orthopedic implant-associated infections to improve the bone healing process. They briefly discuss the clinical course of implant failure, with a prime focus on orthopedic implants. They identify the different anti-infective coating strategies and hence several anti-infective agents which could be incorporated in the hydrogel matrix. The fundamental design criteria to be considered while fabricating anti-infective hydrogels for orthopedic implants will be discussed.

They highlight the different hydrogel coatings based on the origin of the polymers involved in light of their antimicrobial efficacy.They summarize the relevant patents reported in the prevention of implant infections, including orthopedics.

Finally, the challenges concerning the clinical translation of the aforesaid hydrogels are described, and considerable solutions for improved clinical practice and better future prospects are proposed.

Graphical Abstract.

With growing age, or due to sudden trauma, the human body loses its natural tendency to repair injured tissues and reaches a stage with a dire need for medical treatment. Some of these unfortunate events include bone-related defects such as osteoarthritis and fracture. Several medical implants have been engineered to repair or replace damaged tissues to restore their lost function. In general, orthopedic implants range from simple bone fracture fixation devices (FFDs) (screws, pins, plates, wires, and intramedullary nails) to complicated total joint replacement (TJR) prosthetics (viz. total hip replacement (THR), total knee replacement (TKR), elbow, shoulder, ankle, femur, finger joints, wrist). Despite rising demands for these implants, the current medical innovations fail to suffice an implant’s ideal characteristics, as they are very much susceptible to microbial adhesion and proliferation, succeeded by biofilm formation. This imposes a severe threat to their overall performance. Uncontrolled biofilm formation is usually accompanied by implant failure or amputation and, in the worst scenario, the death of the patient. The incidence of prosthetic joint infections (PJIs) depends on the joint location, which accounts for knee (3–4%), hip (2–4%), ankle (2–9%), and elbow (∼5%). Infections due to FFDs vary from as low as 0.5–2% in the case of close internal fracture to as high as 30% due to open internal fracture. These data report the incidences occurring in developed nations. More adversely, in developing countries, the prevalence of infection and the mortality rate is much higher than those in developed nations.

Treatment of the infected implant is an expensive and cumbersome process, varying from long-term antibiotic therapy to surgical debridement and implant replacement. Moreover, the revision surgeries provided to replace the primary infected implant increase the risk of persistent infection. The chances of recurrence in the secondary implants after revision surgery are alarmingly high, e.g., ∼ 33% in the case of TJR.

Traditional preventive approaches, including antibiotic prophylaxis, implant design, and aseptic surgical procedures, have succeeded to some extent in reducing the occurrence of implant failures, yet the significantly high incidence of infections is reported worldwide. The main culprit behind the failure of these approaches is reported to be antibiotic resistance, which has become a challenging issue in the prevention of implant-associated infections (IAIs). More adversely, the microbial biofilm evades the host immune system, which otherwise is highly capable of eliminating such opportunistic organisms. The importance of biofilm eradication has been clearly understood for growing implant efficacy and long-term use. In this regard as an alternative, anti-infective hydrogel holds a noteworthy potential to prevent and/or combat the orthopedic infections that emerge after implant fixation. Illustrates various aspects of the anti-infective hydrogels associated with orthopedic implants, encompassing their different components and ideal features crucial to prevent the IAIs. More importantly, the prime mechanism behind their anti-infective performance has been depicted1.

Schematic illustration of anti-infective hydrogels for orthopedic implant associated infections.

A number of publications related to hydrogels using definite keywords: antibacterial implant hydrogel, orthopedic implant hydrogel, and orthopedic implant antibacterial hydrogel with different (a) years and (b) document types.

(A) Methicillin-resistant Staphylococcus aureus (S. aureus) (MRSA)-infected total hip replacement (THR) and revision surgery to remove necrotic bone and biofilm colonized hardware components. (a–c) Single-stage revision surgery for the infected hardware. (a) Preop X-ray shows septic THR in the periosteal reaction and a nonunited femoral fracture (yellow arrows). (b) Infected thigh opened to undergo removal of necrotic soft tissue and dead bone (white) (adjacent to live bone (red)). (c) Postop X-ray shows femoral defect with the modular hip prosthesis. (d, e) Bacterial biofilm on MRSA-infected hardware components. Photographs of the surface of a femoral total knee replacement component before (d) and after (e) osmium tetroxide staining identify MRSA biofilm on the bone cement.

(A) Schematics illustration of the vital components of PhotothermAA gel for the treatment of Staphylococcus aureus biofilms developed on the titanium (Ti) disk surfaces. (B–E) Assessment of the antibiofilm efficiency of PhotothermAA gel. (B) Experimental setup for PhotothermAA gel treatment of biofilms on the Ti disks, using an 808 nm laser with 1 W/cm2 power intensity and laser spot size of 1 cm2. (C–D) Crystal violet staining assay performed to visualize the residual biofilm on the photothermally treated Ti disks. (C) Images of the residual biofilms. (D) Graph to compare the residual biofilm after the treatment of Ti disks with different conditions. (n = 3): positive control, untreated Ti disks; negative control, no biofilm grown; an asterisk (*) denotes that the differences in means of the treatments are statistically significant at p < 0.05, and NS indicates that the PhotothermAA gel treatment is not statistically significant compared with the negative control at p > 0.05.

(A) Vancomycin (Vanco) loaded hydrogel coated on titanium (Ti) implants involved in the prevention of bone infections. (i) Schematic representation. (ii) SEM micrographs revealing surface morphologies of (a) Ti foil, (b) polydopamine (PDA) coated Ti, (c) Ti-PDA-Gel, and (d) Ti-PDA-Gel-polyethylene glycol-poly(lactic-co-caprolactone (PEG-PLC). The insets show digital photographs of the Ti at different treatment stages. (iii) Radiographic images of the infected bones treated with coated Ti implants with varying antibiotic concentrations (2 and 4 mg); at 1 and 2 weeks after implantation. Dotted red circles indicate the site of the Ti implant. (B) Gentamicin-loaded hydrogel prevents infections in a rabbit humerus osteotomy model. (a) Radiograph of the rabbit humerus osteotomy model, including a fracture fixation plate. S. aureus inoculated on the top of screws (S3 and S4) and in the osteotomy (OS). Gentamicin loaded poly(N-isopropylacrylamide) (nIPAm)-hyaluronic acid (HApN) hydrogel was injected in the OS gap and on top of the plate and allowed to spread through the wound before gelling. (b) Contact radiographs and Giemsa-eosin-stained overview images of the completely operated rabbit humeri depicting the osteotomy and all six screw holes (S1–S6, 4 weeks postoperative, longitudinal cutting plane, fracture fixation implants removed, situation after mechanical testing).

DAC hydrogel coated on an acetabular cup prosthesis. (A–E) Antibiotic loaded hydrogel coating spread onto (A) a stem and (B–C) an acetabular cup and either (D) applied directly on the bone in a routine manner or (E) additionally spread on the extra-medullary part of the acetabular cup. (F–G) Scanning electron microscopy (SEM) micrographs of the sand-blasted prosthesis surface: (F) prior to DAC coating and (G) after coating, showing complete surface coverage of the prosthesis.

  1. Garg, D., Matai, I., & Sachdev, A. (2021). Toward Designing of Anti-infective Hydrogels for Orthopedic Implants: From Lab to Clinic. ACS biomaterials science & engineering, 10.1021/acsbiomaterials.0c01408. Advance online publication.