Novel Fracture Site Targeting Drug Improves Fracture Healing with Pain Relief: Preclinical Evaluation of MAK123

Non-union bone fracture occurs in 5-10% of fracture injuries. Interventions include surgery with local implantation of autograft, allograft, demineralized bone matrix, and/or bone morphogenetic proteins. These types of fracture injuries are also accompanied by acute and chronic pain states. In most instances, opioids are provided to injured patients during and after surgery. With the opioid crisis, identifying new analgesic therapies that could reduce or eliminate opioid use, while also improving bone healing is important. Here we show the ability of a novel compound, MAK123, to both enhance bone healing and reduce pain behavior in a surgically induced femoral fracture mouse model. Briefly, 20 male C57BL/6 mice underwent a surgically induced femoral fracture and then were treated with 0, 2, 6, or 20 mg/kg, 3X/week for the 3 week study duration. Weekly X-rays were used to examine healing progression. Prior to euthanasia, mice underwent behavioral testing to measure evoked pain behaviors. Upon euthanasia, ex vivo µCT imaging and analysis was completed to assess fracture callus size and composition. While all doses of MAK123 tested resulted in improved healing, the 6mg/kg dose resulted in accelerated bone healing and a significant increase in mineralized callus volume (p<0.05). Similarly, while all doses of MAK123 reduced evoked responses to tactile stimulus as demonstrated by increased paw withdrawal thresholds, 6 mg/kg of MAK123 resulted in a more robust and significant improvement (p<0.05). We postulate that optimization of the dosing schedule/concentration could further improve both bone healing and behavioral measures thought to represent pain in rodents. That said, these promising pre-clinical data warrant further evaluation as MAK123 may prove to be a unique tool for orthopaedic surgery usage whereby it could both improve bone healing and reduce clinical pain, improving overall patient outcomes.

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Augmentation of bone healing of nonunion fracture using stem cell based tissue engineering in a dog: a case report

Veterinární Medicína ◽

10.17221/3024-vetmed ◽

2009 ◽

Vol 54 (No. 4) ◽

pp. 198-203 ◽

Cited By ~ 5

Author(s):

H.B. Lee ◽

Y.S. Chung ◽

S.Y. Heo ◽

N.S. Kim

Keyword(s):

Bone Healing ◽

Bone Fracture ◽

Cell Attachment ◽

Ex Vivo ◽

Bone Matrix ◽

Fracture Site ◽

Adipose Derived Stem Cells ◽

Intact Male ◽

Fracture Fragment ◽

Surgical Failure

A 4-year-old, intact male crossbreed dog, weighing 27 kg, was referred for the treatment of a nonunion fracture. The radiographs revealed displacement of the radius and ulna bone fracture fragment and a sclerotic fracture end of the radius. Autologous adipose derived stem cells (ADSCs) were isolated and expanded ex vivo in a culture. The ADSCs (3.2 × 107 cells) were seeded on a composition scaffold made from hydroxyapatite (HA) and chitosan (CH) fibers. The seeded scaffold with ADSCs was placed on the fracture site and the bone fracture was stabilized. A sample of seeded scaffold with ADSCs was taken to evaluate the extent of cell attachment and morphology on the scaffold using scanning electron microscopy (SEM). SEM showed that ADSCs adhered to the scaffold well and many bone nodules formed from the bone matrix secreted by ADSCs. Three months after surgery, the nonunion had successfully healed with no complications. The application of a composition scaffold of HA and CH containing ADSCs can be used to treat a nonunion fracture by augmenting bone healing and may decrease the risk of surgical failure of nonunion fractures.

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MAK122: A Novel Drug Utilizing Innovative Fracture Site Targeting Technology to Improve Bone Healing

Proceedings of IMPRS ◽

10.18060/25922 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Nicholas Hux ◽

Jeffery Nielson ◽

Caio De Andrade Staut ◽

Vincent Alentado ◽

Abduallah Elsayed ◽

...

Keyword(s):

Fracture Healing ◽

Bone Healing ◽

Ex Vivo ◽

Healing Process ◽

Fracture Site ◽

Fracture Repair ◽

X Rays ◽

Invasive Treatment ◽

Post Surgery ◽

Novel Drug

Megakaryocytes play a pivotal role in the bone fracture healing process through enhancing osteoblast proliferation, osteoclastogenesis, and angiogenesis. Current fracture repair therapies require direct implantation during surgery (BMP-2, grafts etc.), which has limitations. In order to address this, a novel drug, compound MAK122, was created with targeting technology that directs its actions to the fracture site without needing to be implanted during surgery, limiting undesirable offsite effects, increasing the quantity of drug at the fracture site, and allowing for non-invasive treatment following assessment of the natural healing process. Therefore, this study examined the ability of MAK122 to stimulate megakaryocytes and subsequent bone healing. To accomplish this, male mice on a C57BL/6 background underwent a surgically induced femoral fracture. Following surgery, the mice were injected daily for the first 7 days with either saline (vehicle) or MAK122. Mice were then euthanized 2, 3 and 4 weeks post-surgery. Fracture healing was assessed by standard and novel methodologies. Biweekly X-rays were evaluated and bone union was scored showing that MAK122 accelerated bone healing compared to controls. Ex vivo µCT analysis demonstrated that MAK122 increased callus volume and the percentage of mineralized callus tissue compared to vehicle treatment. Biomechanical testing showed that MAK122 treatment resulted in stronger repairs as compared to vehicle treated controls with nearly a 2-fold increase in twist to failure and toughness parameters. Additionally, histological assessment demonstrated accelerated remodeling in MAK122 treated femurs compared to those treated with saline. Taken together, these pre-clinical data suggest that MAK122 is capable of promoting an environment in which megakaryocytes can favorably influence bone remodeling mechanisms, expediting fracture repair in murine models. Though further pharmacokinetic, pharmacodynamic, and toxicology studies are required, MAK122 displays potential to serve as a state-of-the-art therapy for improving fracture healing in humans.

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First Human Leucocyte Antigen (HLA) Response and Safety Evaluation of Fibrous Demineralized Bone Matrix in a Critical Size Femoral Defect Model of the Sprague-Dawley Rat

Materials ◽

10.3390/ma13143120 ◽

2020 ◽

Vol 13 (14) ◽

pp. 3120

Author(s):

Nicolas Söhling ◽

Maximilian Leiblein ◽

Alexander Schaible ◽

Maren Janko ◽

Joachim Schwäble ◽

...

Keyword(s):

Bone Healing ◽

Critical Size ◽

Demineralized Bone Matrix ◽

High Surface ◽

Bone Matrix ◽

Volume Ratio ◽

Bone Allograft ◽

Control Group ◽

Sprague Dawley ◽

Demineralized Bone

Treatment of large bone defects is one of the great challenges in contemporary orthopedic and traumatic surgery. Grafts are necessary to support bone healing. A well-established allograft is demineralized bone matrix (DBM) prepared from donated human bone tissue. In this study, a fibrous demineralized bone matrix (f-DBM) with a high surface-to-volume ratio has been analyzed for toxicity and immunogenicity. f-DBM was transplanted to a 5-mm, plate-stabilized, femoral critical-size-bone-defect in Sprague-Dawley (SD)-rats. Healthy animals were used as controls. After two months histology, hematological analyses, immunogenicity as well as serum biochemistry were performed. Evaluation of free radical release and hematological and biochemical analyses showed no significant differences between the control group and recipients of f-DBM. Histologically, there was no evidence of damage to liver and kidney and good bone healing was observed in the f-DBM group. Reactivity against human HLA class I and class II antigens was detected with mostly low fluorescence values both in the serum of untreated and treated animals, reflecting rather a background reaction. Taken together, these results provide evidence for no systemic toxicity and the first proof of no basic immunogenic reaction to bone allograft and no sensitization of the recipient.

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