Intradiscal application of a PCLA–PEG–PCLA hydrogel loaded with celecoxib for the treatment of back pain in canines: What's in it for humans?

Abstract

Chronic low back pain is a common clinical problem in both the human and canine population. Current pharmaceutical treatment often consists of oral anti-inflammatory drugs to alleviate pain. Novel treatments for degenerative disc disease focus on local application of sustained released drug formulations. The aim of this study was to determine safety and feasibility of intradiscal application of a poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-bpoly(ε-caprolactone-co-lactide) PCLA-PEG-PCLA hydrogel releasing celecoxib, a COX-2 inhibitor. Biocompatibility was evaluated after subcutaneous injection in mice, and safety of intradiscal injection of the hydrogel was evaluated in experimental dogs with early spontaneous intervertebral disc (IVD) degeneration. COX-2 expression was increased in IVD samples surgically obtained from canine patients, indicating a role of COX-2 in clinical IVD disease. Ten client-owned dogs with chronic low back pain related to IVD degeneration received an intradiscal injection with the celecoxib-loaded hydrogel. None of the dogs showed adverse reactions after intradiscal injection. The hydrogel did not influence magnetic resonance imaging signal at long-term follow-up. Clinical improvement was achieved by reduction of back pain in 9 of 10 dogs, as was shown by clinical examination and owner questionnaires. In 3 of 10 dogs, back pain recurred after 3 months. This study showed the safety and effectiveness of intradiscal injections in vivo with a thermoresponsive PCLA-PEG-PCLA hydrogel loaded with celecoxib. In this set-up, the dog can be used as a model for the development of novel treatment modalities in both canine and human patients with chronic low back pain.

Leaping the hurdles in developing regenerative treatments for the intervertebral disc from preclinical to clinical

“…A number of preclinical small animal models that mimic specific aspects that contribute to low back pain (LBP) has been recently reviewed by Shi et al Pain measurements in large animal models are primarily qualitative and deduced from objective gait analysis that does not allow for the exact (spinal) localization . Specifically in the case of dog patients with chronic back pain employed as a model for humans within the concept of “One Medicine,” owners can fill in questionnaires regarding pain assessment aspects and inherent impairment of mobility as would humans entering a clinical trial . Despite the difficulties, when evaluating the success of any potential therapy in animal models, it is recommended that some measure of biomechanical function and pain assessment, appropriate to the selected animal model, is performed.…”

“…To our knowledge, this has only been developed for mice and dogs . In terms of imaging, large animal models have rather similar possibilities as humans with LBP: radiography, fluoroscopy, discography, computer tomography (CT), and magnetic resonance imaging (MRI) . However, there are some drawbacks.…”

The chondrodystrophic dog: A clinically relevant intermediate‐sized animal model for the study of intervertebral disc‐associated spinal pain

“…Within the field of tissue engineering, several cell seeded hydrogels have been proposed to treat IVDD, which include replacement of the entire or part of the disc in in vivo or mainly for use as drug control release systems. Some examples are biocompatible hydrogels such as PCLA‐PEG‐PCLA (poly(ε‐caprolactone‐co‐lactide)‐b‐poly(ethylene glycol)‐bpoly(ε‐caprolactone‐co‐lactide)), agarose, and polyester amides . Additionally, hydrogels have also been used to encapsulate drugs for delivery into the IVD …”

“…Some examples are biocompatible hydrogels such as PCLA‐PEG‐PCLA (poly(ε‐caprolactone‐co‐lactide)‐b‐poly(ethylene glycol)‐bpoly(ε‐caprolactone‐co‐lactide)), agarose, and polyester amides . Additionally, hydrogels have also been used to encapsulate drugs for delivery into the IVD …”

“…Some examples are biocompatible hydrogels such as PCLA-PEG-PCLA (poly(ε-caprolactone-co-lactide)-b-poly(ethylene glycol)-bpoly(ε-caprolactone-co-lactide)), agarose, and polyester amides. [104][105][106] Additionally, hydrogels have also been used to encapsulate drugs for delivery into the IVD. [105][106][107] These various therapies, as summarized, demonstrate the potential of the CD dog model as a clinically relevant model to evaluate regenerative IVDD therapies which can later translate to human conditions.…”