Repair and regeneration of the critically injured peripheral nerves is one of the most challenging reconstructive surgeries. Currently available and FDA approved nerve guidance channels (NGCs) are suitable for small gap injuries, and their biological performance is inferior to that of autografts. Development of biomimetic NGCs with clinically relevant geometrical and biological characteristics such as topographical, biochemical and haptotactic cues could offer better regeneration of the long gap complex nerve injuries. Here, in this study, we present the development and preclinical analysis of a 3D printed aligned cryomatrix filled NGCs along with nerve growth factor (NGF) (aCG+NGF) for peripheral nerve regeneration. We demonstrated the application of these aCG+NGF NGCs in the enhanced and successful regeneration of a critically injured rat sciatic nerve in comparison to random cryogel filled NGCs, multichannel, and clinically preferred hollow conduits as well as gold standard autografts. Our results indicated viz-a-viz similar effect of aCG+NGF NGCs to that of autografts, and not only enhanced the overall regenerated nerve physiology, but could also mimic the cellular aspects of regeneration. This study emphasizes the paradigm that these biomimetic 3D printed NGCs will lead to a better functional regenerative outcome under clinical settings.
Hip fractures are among the most common types of fracture risks in old age osteoporotic patients that often end up with immobile disabilities. Weak bones due to loss of mineral content along with an increase in the porosity of the femur neck canal in osteoporosis reduce the mechanical properties of the bone and predispose the patients to fractures. In this study, we have used calcium sulfate/nanohydroxyapatite based nanocement (NC) as carrier of recombinant human bone morphogenetic protein-2 (BMP-2), zoledronate (ZA), and bone marrow mesenchymal stromal cells (MSCs) derived exosomes (EXO) to enhance bone formation and defect healing in a femur neck canal defect model in osteoporotic rats. A cylindrical defect in the femur neck canal with dimensions of 1 mm (diameter) × 8 mm (length) starting from the lateral cortex toward the apex of the femur head was developed. The defect was impacted using NC alone or functionalized as (a) NC + ZA (systemic), (b) NC + ZA (local), (c) NC + EXO + ZA, and (d) NC + BMP + ZA to evaluate bone formation by ex vivo micro-computed tomography (micro-CT) and histological analysis 16 weeks postsurgery. Moreover, the femurs (both defect and contralateral leg) were subjected to biomechanical analysis to assess the effect of treatments on compressive mechanical properties of the bones. The treatment groups (NC + ZA (L), NC + BMP + ZA, and NC + EXO + ZA) showed enhanced bone formation with complete healing of the defect. No differences in the mechanical properties of both the defect and contralateral across the leg were observed among the groups. However, a trend was observed where NC + BMP + ZA showed enhanced biomechanical strength in the defect leg. This suggests that NC could act as a potent carrier of bioactive molecules to reduce the risks of hip fractures in osteoporotic animals. This type of treatment can be given to patients who are at higher risk of osteoporosis mediated femur neck fracture as a preventive measure or for enhanced healing in already compromised situations. Moreover, this study provided a proof of concept regarding the use of exosomes in bone regeneration therapy, which might be used as a booster dose that will eventually reduce the dosage of BMP and hence circumvent the limitations associated with the use of BMP.
Long term multiple systemic antibiotics form the cornerstone in the treatment of bone and joint tuberculosis, often combined with local surgical eradication. implanted carriers for local drug delivery have recently been introduced to overcome some of the limitations associated with conventional treatment strategies. in this study, we used a calcium sulphate hemihydrate (cSH)/ nanohydroxyapatite (nHAP) based nanocement (NC) biomaterial as a void filler as well as a local delivery carrier of two standard of care tuberculosis drugs, Rifampicin (Rfp) and isoniazid (inH). We observed that the antibiotics showed different release patterns where INH showed a burst release of 67% and 100% release alone and in combination within one week, respectively whereas RFP showed sustained release of 42% and 49% release alone and in combination over a period of 12 weeks, respectively indicating different possible interactions of antibiotics with nHAP. The interactions were studied using computational methodology, which showed that the binding energy of nHAp with Rfp was 148 kcal/mol and INH was 11 kcal/mol, thus varying substantially resulting in RFP being retained in the nHAP matrix. Our findings suggest that a biphasic ceramic based drug delivery system could be a promising treatment alternative to bone and joint tB. Tuberculosis (TB) is a global disease that caused an estimated 1.2 million deaths in 2018 and around 10 million new TB cases were reported globally in the same year, with the incidence being stable in the recent years as per World Health Organization (WHO) report 1 Osteoarticular tuberculosis is a common manifestation accounting for 10-15% of all extrapulmonary TB (EPTB) 2,3 cases and 1-4% of all TB cases 4-6. The bone and joint TB is most often found in spine and weight bearing extremities resulting in neurological complications and joint destruction 7. Treatment modalities include surgical debridement of bone lesions, instrumental stabilisation and filling of dead space with allografts or autograft as well as systemic administration of anti-tuberculosis drugs (ATDs) like Isoniazid (INH), Rifampicin (RFP), Pyrazinamide (PZA), Ethambutol (EMB) and Streptomycin (SM). However, multiple drug resistance and TB recurrence has made it necessary to adhere to long-term, systemic oral use of multiple anti-tuberculosis drugs 8,9. Long-term systemic administration of first line drugs
Polymer (acrylate) and ceramic bone cements are extensively used as bone void fillers and for implant fixation in orthopedics. These materials have micro- to nonporous architectures. Postimplantation, they may cause hypoxic and exothermic injuries to already compromised damage site. These materials also have limited interaction with surrounding tissue. In this work we have developed composite collagen-nanohydroxyapatite (CS) bone filler, mimicking porous architecture of trabecular bone. It was functionalized with clinically available bone active agents like bone morphogenetic protein-2 (rhBMP-2) and zoledronic acid (ZA). We investigated synergistic effects of the bone active molecules and endogenous platelet rich plasma (PRP), a source of growth factors on mineralization. Porous CS and collagen/gelatin/chiotosan polymer scaffold (SC) (without nanohydroxyapatite) were synthesized using cryogelation. PRP (10 μL) (∼5 × 106 cells), rhBMP-2 (5 μg) and ZA (10 μg) were used to functionalize scaffolds. Bone formation was evaluated at ectopic sites in abdominal pouch and 4.0 mm critical defect in tibia metaphysis of rats. Tissue mineralization was evaluated by micro-CT and histological analysis 12 weeks postimplantation. In vitro cell based studies revealed, PRP functionalization enhances osteoblast proliferation and activity on scaffolds. In vivo BMP+ZA+PRP functionalized scaffolds had higher amount (28 mm3) of mineralized tissue formation as compared to empty defect (20 mm3), suggesting that PRP can augment the osteoinductive properties of functionalized scaffolds both in vitro and in vivo. Enhanced cell infiltration and mineralization can be achieved via CS in comparison to SC, implying their use as porous bone void fillers and substitutes for autografts.
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