Biomaterials, Fracture Healing, Orthopedic Implants, Osteoporosis, Drug delivery in Cancer and Infections.
Fracture fixation and bone repair research are one of the strengths of the TERM Lund group.
During the natural course of bone healing, after the early inflammation subsides, a collagenous tissue template is built up around the fracture. Progenitor cells, biomolecules (growth factors) and the tissue together orchestrate scar free healing of bone. There are certain situations where the natural process is not enough to give complete bone healing.
This can happen after major trauma to the bone, where large volumes of bone need to be repaired or in pathological conditions such as tumors, infection and osteoporosis.
Osteoporosis leads to bone quality deterioration over time, which in-turn make patients prone to fragility fractures. In such conditions, pharmacological primary or secondary prevention and fracture fixation remain the choice. Most of the osteoporotic fractures require to be internally stabilized using implants in the form of metal plates and screws. Due to the low mechanical quality of the native diseased bone, the anchorage of these implants is less than optimal, which eventually leads to the failure of the implant fixation and even re-operations.
Our group focuses on strengthening osteoporotic bones and preventing fractures as well as using regenerative medicine techniques to enhance implant anchorage in osteoporotic bone. We use biomaterials (ceramics, polymer-ceramic composites) for local controlled delivery of bioactive cues (growth factors/drugs) that aids in regenerating the missing bone tissue.
A more recent field of research has been to use ceramic biomaterials embedding micro and nano hydroxyapatite (HA) to recruit systemically administered drugs. Due to a unique structure of the HA crystal specific pharmaceutical agents administered systemically seek and bind to HA particles and exert a unique biological effect favourable for treating the bone disease.
Our current areas of research in the field of bone regeneration include:
- Fabrication and characterization of novel bone mimicking biomaterials
- Spatio-temporal local delivery of bone active molecules
- Experimental bone healing animal models in healthy and osteoporotic animals including long-bone regeneration, lumbar fusion and non-union models.
Biomaterials based local or targeted delivery of chemotherapeutic agents is one of the important research areas of our lab. Recent clinical studies have shown that intensifying chemotherapy by combining several anti-cancer agents together does not improve the event-free survival in solid tumors but causes more side effects. Our aim is to send the drugs to the targeted site (tumor tissue) by using hydroxyapatite (HA)-based materials to act as a recruiting moiety for systemically circulating drugs and achieve more efficient tumor-killing with less off-target effects.
Ever since the use of aggressive chemotherapy drugs was introduced 30 years ago, the event free survival in patients has significantly improved. However, an increasing drug resistant pattern in sarcoma patients has been seen in the past 5-10 years. Sarcomas has a microenvironment with a high interstitial fluid pressure and neo-angiogenesis blocking the drugs reaching the tumor tissue, which leads to both inefficient tumor killing and drug resistance. Systemically circulating anti-cancer agents tend to accumulate in the liver, lung and heart causing severe side effects.
No new drug has been discovered for the treatment of sarcomas (in particular, osteosarcoma) and inventing a new anti-cancer agent need more than 15-20 years of lab research and clinical trials.
Thus, using biomaterials to deliver already approved repurposed drugs more efficiently might be the alternative for a rapid translation from the bench to bedside. Furthermore, providing a HA based recruiting platform that can lead to accumulation of high doses of the chemotherapy drugs opens up new avenues of targeted tumor delivery and minimizing side effects.
Our previous data have shown local controlled and sustained delivery (up to 28 days) of doxorubicin (DOX) using an HA based biomaterial has a better tumor-killing effect than systemic injection. Further, various anti-cancer agents combing with DOX are being explored in the lab now to achieve a spatial release to cover a longer treatment period. Later locally implanted slow resorbing hydroxyapatite could be used as a Trojan horse within the tumor to reload circulating apatite-binding drugs like DOX in the long follow-up to prevent recurrence and complement present systemic treatment.
Our current areas of research in the field of bone cancer include:
- Spatio-temporal controlled local delivery of various first-line anti-cancer agents
- Explore the interactions between anti-cancer agents and hydroxyapatite to screen for more HA binding drugs
- Explore intracellular delivery of anti-cancer agents by nanomaterials to boost its efficacy
- Construct human sarcoma in animal models to test the efficacy of our treatment on both immunodeficient and immunocompetent mice, including subcutaneous xenograft, orthotopic xenograft and patient derived xenografts (PDX).
Deep bone infection is the most serious complication in orthopaedic surgery. In these infections, achieving an adequate local concentration of antibiotics is a challenge. Using the current treatment methods like long-term systemic antibiotics following local debridement, effective antibiotic levels may not reach the desired target and also lead to serious toxicities and the selection of antibiotic-resistant bacteria.
Excellent long-term outcome has been reported in chronic osteomyelitis by radical debridement and filling the dead space with a gentamycin containing calcium sulphate/ hydroxyapatite (CaS/HA) bone substitute. High local concentrations can be reached by the elution of the antibiotic concomitant with the resorption of calcium sulphate during the first postoperative weeks.
However, in extensive infections, sessile bacteria may remain in bone cells and adjacent cortical bone or soft tissue protected by biofilm and lead to recurrences. In order to shorten the antibiotic treatment and to achieve high concentrations at MIC levels, surgeons in the last few decades have used local delivery of antibiotics added to PMMA bone cements.
However, antibiotic containing PMMA does not give sustained release and lacks bone regeneration properties. No biomaterial however currently contains and delivers Rifampicin, an apatite binding antibiotic considered as cornerstone second defence antibiotic in the treatment of severe longstanding deep bone and joint prosthetic infections.
Our group is aiming to contribute to solving this problem by delivering using specific apatite binding drugs using ceramic carriers containing particulate apatite particles. This could help to achieve clinically relevant local concentrations evading systemic side effects. Another area of infection in which TERM group focusing is novel treatment modalities to prevent relapses or chronicity in bone infections.
We are exploring the potential of hydroxyapatite particles pre-functionalized with specific antibiotics as a novel method for eradicating intracellular reservoirs of bacteria. The known ability of nano-sized particles of hydroxyapatite to penetrate cells could help the clinicians to achieve high release of antibiotics intracellularly. The use of HA based nano particles also opens up the possibility of sending and repeatedly reload systemic antibiotics to implanted HA particles.
Our current areas of research in the field of bone infection include:
Explore drug accretion to apatite screening for additional anti-infectious agents evading resistance .
- Explore intracellular delivery of apatite nano materials containing anti-infectious agents to boost MIC and MBEC efficiency.