The selective cathepsin K inhibitor MIV-711 attenuates joint pathology in experimental animal models of osteoarthritis.

BACKGROUND: MIV-711 is a highly potent and selective cathepsin K inhibitor. The current article summarizes the therapeutic effects of MIV-711 on joint pathology in rabbits subjected to anterior cruciate ligament transection (ACLT), and the prophylactic effects on joint pathology in dogs subjected to partial medial meniscectomy, two surgical models of osteoarthritis (OA). METHODS: Starting 1 week after surgery, rabbits were dosed daily via oral gavage with either MIV-711 or vehicle (n = 7/group) for 7 weeks. The four treatment groups were: (1) sham + vehicle; (2) ACLT + vehicle; (3) ACLT + MIV-711, 30 µmol/kg and (4) ACLT + MIV-711, 100 µmol/kg. Subchondral bone and articular cartilage structures were assessed by µCT, histomorphometry, and scoring. Dogs subjected to partial medial meniscectomy received either MIV-711 (30 µmol/kg) or vehicle (n = 15/group) via oral gavage once daily, starting 1 day before meniscectomy, for 28 days. Cartilage degradation was assessed at the macroscopic and microscopic levels. The exposures of MIV-711 were assessed in both studies and biomarkers reflecting bone resorption (HP-1 in rabbits, CTX-I in dogs) and cartilage degradation (CTX-II) were measured. RESULTS: In ACLT rabbits, MIV-711 decreased HP-1 levels by up to 72% (p < 0.001) and CTX-II levels by up to 74% (p < 0.001) compared to ACLT vehicle controls. ACLT surgery significantly reduced the total thickness of the subchondral bone plate and reduced trabecular bone volume in the femur and tibia. These effects were reversed by MIV-711. ACLT resulted in cartilage thickening, which was attenuated by MIV-711. MIV-711 did not affect osteophyte formation or Mankin scores. In dogs, MIV-711 reduced CTX-I and CTX-II levels by 86% (p < 0.001) and 80% (p < 0.001), respectively. Synovial CTX-II levels were reduced by 55-57% (p < 0.001) compared to baseline. MIV-711-treated animals had 25-37% lower macroscopic scores in the femur condyles and 13-33% lower macroscopic scores in the tibial plateaus. CONCLUSIONS: MIV-711 prevents subchondral bone loss and partially attenuates cartilage pathology in two animal models of OA. These beneficial effects of MIV-711 on joint pathology are observed in conjunction with decreases in bone and cartilage biomarkers that have been shown to be clinically attainable in human. The data support the further development of MIV-711 for the treatment of OA.

Comparison of V-Loc™ 180 wound closure device and Quill™ PDO knotless tissue-closure device for intradermal closure in a porcine in vivo model: evaluation of biomechanical wound strength.

OBJECTIVE: The objective of this study was to compare the biomechanical strength of two barbed suture devices: V-Loc™ 180 Wound Closure Device and Quill™ PDO Knotless Tissue-Closure Device following primary cosmetic skin closures in a porcine dermal model. METHOD: This prospective randomized, controlled in vivo trial compared size 3/0 V-Loc™ 180 device to size 2/0 Quill™ PDO device. Both products were tested for dermal closure in adult porcine models and evaluated at five timepoints. At postoperative days 0, 3, 7, 14, and 28 sutured tissue regions were excised post mortem and tested for intradermal wound holding strength. RESULTS: Wounds closed with V-Loc™ 180 device were stronger than Quill™ PDO device at days 0, 3, 7, and 14 with these differences being significant (p < 0.05) at days 3 and 7. At day 3, the average maximum load of V-Loc™ 180 was 13.53 kgf and Quill™ PDO was 10.38 kgf (p = 0.002). At day 7, the average maximum load of V-Loc™ 180 was 10.4 kgf and Quill™ PDO was 7.56 kgf (p = 0.001). Throughout the duration of the study, there was no suture extrusion or tissue distortion and all wounds healed with no major complications. CONCLUSIONS: In this study, V-Loc™ 180 device was significantly stronger than Quill™ PDO device during the critical phases of wound healing in skin.

An in vivo comparison of barbed suture devices and conventional monofilament sutures for cosmetic skin closure: biomechanical wound strength and histology.

BACKGROUND: Very little biomechanical or histological data exist in the peer-reviewed literature comparing absorbable monofilament sutures to commercially-available knotless, absorbable barbed suture devices for cosmetic closure of skin incisions. OBJECTIVES: The authors compare two commercially-available knotless, barbed suture devices against a conventional monofilament suture in a porcine model for biomechanical wound strength and histological quality of healing. METHODS: This prospective randomized trial included 18 animals randomly assigned among three groups, with six in each. A total of 192 incisions were closed in a porcine in vivo model and assessed for biomechanical strength and histology at postoperative Days 0, 3, 10, and 21. Each animal received all three test devices in a randomized, three-way matched design. Immediately following euthanasia, the skin incisions were excised for ex vivo biomechanical testing. RESULTS: In the ex vivo analysis, Biosyn proved significantly stronger than the V-Loc 90 device at Day 0 and Quill Monoderm at Day 3. At no time point was there any difference in biomechanical strength between the two barbed suture devices. Differences in barb geometry, barb number, and helicity between the two barbed suture devices resulted in failure modes that were significantly different. All three test articles resulted in mild tissue reaction scores on histology. The V-Loc 90 device consistently had the lowest tissue reaction scores at all time periods, with the difference between the V-Loc 90 device and Quill being significant at postoperative Day 10. CONCLUSIONS: Knotless, absorbable barbed suture devices are a safe and efficacious alternative for cosmetic skin closures and yield wound strength and tissue reaction scores that are comparable to those from closures performed with absorbable monofilament sutures and secured with knots.

Species-specific assessment of pain in laboratory animals.

Pain has been defined by the International Association for the Study of Pain as "an unpleasant sensory and emotional experience associated with actual or potential damage or described in terms of such damage". However, the ability to describe the concept of pain is difficult largely because pain is an individualized and subjective experience. What one person finds painful, another may not; what relieves pain for one may not do so for another. Awareness of pain management has become an important health issue for humans and animals. To effectively manage pain, it is crucial to be able to identify it, and identification of pain in animals can be especially problematic. Recognition and alleviation of pain in animals used in biomedical research and teaching is an important goal, both from a humane and regulatory perspective. This paper will: 1) review current literature regarding pain assessment using pain scales and 2) describe how an institutional care and use committee (IACUC) has implemented an effective pain scoring system to allow for an objective, accurate, and humane assessment of pain experienced by animals used in biomedical research.