Improving biological integration of osseous and dermal tissues in macaque cranial implants
Lead Research Organisation:
Newcastle University
Department Name: Biosciences Institute
Abstract
Non-human primates (NHPs) are an indispensable model in neuroscience research. Their brains are sufficiently similar to our own that they can provide important insights into how the human brain works, which can help to develop a variety of medical treatments. Unlike research with humans, it is possible to use invasive techniques in NHPs, to understand how neurons are organized, how they communicate, and which brain chemicals mediate their communication. Many of the studies employing NHPs require surgical implantation of a headpost and a recording chamber under general anaesthesia. These 'cranial implants' are required to keep the animals' heads motionless during experiments in order to obtain functional magnetic resonance imaging (fMRI) data or electrophysiological recordings. The implants are anchored to the skull by means of surgical screws, and the skin is closed around them. The implants generally integrate well with the underlying bone, due to the use of modern biocompatible materials. However, they often suffer from imperfect skin closure around the part of the implant that is exposed. Imperfect skin closure often results in infection of the skin and other soft tissue, which can lead to skin retraction and extension of the wound margin. Animals may need their wounds regularly cleaned once infected, and where infections prove difficult to clear, they may infect the bone and lead to implant loss. Consequently, there is an urgent need to refine the designs of cranial implants in order to reduce the health risks to the animals, and significantly improve animal welfare. These developments should be centred on improving the integration of soft tissue and skin with the implant, in order to prevent and reduce implant infection and its associated complications.
We will use recent developments in human clinical studies (and animal preclinical studies) that have improved soft tissue integration in prostheses that have similar requirements to cranial implants, i.e. they need to be anchored to the bone, but protrude through the skin. By adding specific porous materials and/or changing the shape of those parts of the implant that are in direct contact with the skin, skin cells more effectively anchor to the implant, which improves wound healing. The success of these approaches has been outstanding, but they have yet to be applied to the use of primate cranial implants. By adding porous materials to existing implant designs for NHPs, our aim is to substantially improve the integration of the skin with the implant, thereby reducing inflammation and infection rates, and improving animal welfare. Importantly, our approach employs novel techniques for implant production (3-D printing), which can now produce implants using the most biocompatible materials (e.g. zirconium ceramics, hydroxyapatite), which are tailored to each individual animal. This printing technology is also now widely available, ensuring that neuroscience laboratories worldwide will be able to produce similar implants for their own animals. To ensure this, we will develop an instruction and software package (a 'workflow'), that is open source, and easy and cheap to implement by different laboratories, so they can generate their own 3-D printing model, starting with a 3-D MRI model of the animal skull and a basic outline sketch of an implant of the desired shape. We predict that our project will reduce infection rates, reduce discomfort associated with infected implants, reduce instances of implant failure, and significantly improve animal welfare. It will also potentially lead to some reductions in the numbers of animals used, by increasing the quality and quantity of scientific data obtained, as fewer animals will be necessary to obtain a scientific objective.
We will use recent developments in human clinical studies (and animal preclinical studies) that have improved soft tissue integration in prostheses that have similar requirements to cranial implants, i.e. they need to be anchored to the bone, but protrude through the skin. By adding specific porous materials and/or changing the shape of those parts of the implant that are in direct contact with the skin, skin cells more effectively anchor to the implant, which improves wound healing. The success of these approaches has been outstanding, but they have yet to be applied to the use of primate cranial implants. By adding porous materials to existing implant designs for NHPs, our aim is to substantially improve the integration of the skin with the implant, thereby reducing inflammation and infection rates, and improving animal welfare. Importantly, our approach employs novel techniques for implant production (3-D printing), which can now produce implants using the most biocompatible materials (e.g. zirconium ceramics, hydroxyapatite), which are tailored to each individual animal. This printing technology is also now widely available, ensuring that neuroscience laboratories worldwide will be able to produce similar implants for their own animals. To ensure this, we will develop an instruction and software package (a 'workflow'), that is open source, and easy and cheap to implement by different laboratories, so they can generate their own 3-D printing model, starting with a 3-D MRI model of the animal skull and a basic outline sketch of an implant of the desired shape. We predict that our project will reduce infection rates, reduce discomfort associated with infected implants, reduce instances of implant failure, and significantly improve animal welfare. It will also potentially lead to some reductions in the numbers of animals used, by increasing the quality and quantity of scientific data obtained, as fewer animals will be necessary to obtain a scientific objective.
Technical Summary
Neuroscience involving primates often requires cranial implants, allowing an animal's head to be stabilized for neural recordings or imaging. Implants can suffer from poor dermal integration, resulting in inflammation or infection, and thus have a negative impact on the animals. In the worst case, it results in bone necrosis and implant loss. There is thus an urgent need to develop new implants which reduce health risks to the animals and improve animal welfare.
Our proposed cranial implant design builds on advances in human percutaneous ('extending through the skin') medical prosthesis. Here, adhesion of skin to exteriorized bone implants is significantly improved by adding a perforated flange, or an area of increased porosity to implant parts that are in direct contact with the closing skin. It significantly reduces infection and complication rates. Copying this approach to individually tailored cranial implants, we expect to obtain similar benefits for primates used in neuroscience.
To achieve this, and promote widespread uptake by the community, we will develop an instruction and software package (a 'workflow'), allowing ourselves and other researchers to easily generate 3-D computer implant models, with detailed surface porosity characteristics, from which medical grade CAD machined or 3-D printed implants can be manufactured.
Empirically, we will assess dermal integration of different cranial implant designs and materials in ~32 animals, all with either an added perforated flange or increased porosity. Using clinical, microbiological, and histopathological data we will compare implant integration and wound margin closure against our large sample of previous implants. We predict that overall dermal and osseous integration rate will be increased and infection rates will be reduced. This refinement will lead to significant increases in animal welfare, and reduce the number of animals used by improving data quality and quantity from individual subjects.
Our proposed cranial implant design builds on advances in human percutaneous ('extending through the skin') medical prosthesis. Here, adhesion of skin to exteriorized bone implants is significantly improved by adding a perforated flange, or an area of increased porosity to implant parts that are in direct contact with the closing skin. It significantly reduces infection and complication rates. Copying this approach to individually tailored cranial implants, we expect to obtain similar benefits for primates used in neuroscience.
To achieve this, and promote widespread uptake by the community, we will develop an instruction and software package (a 'workflow'), allowing ourselves and other researchers to easily generate 3-D computer implant models, with detailed surface porosity characteristics, from which medical grade CAD machined or 3-D printed implants can be manufactured.
Empirically, we will assess dermal integration of different cranial implant designs and materials in ~32 animals, all with either an added perforated flange or increased porosity. Using clinical, microbiological, and histopathological data we will compare implant integration and wound margin closure against our large sample of previous implants. We predict that overall dermal and osseous integration rate will be increased and infection rates will be reduced. This refinement will lead to significant increases in animal welfare, and reduce the number of animals used by improving data quality and quantity from individual subjects.
Planned Impact
The main impact will be a refinement in technique of chronical exteriorized cranial implants, that benefits animal welfare, and the science conducted in these animals, thereby also resulting in potential reductions in animal numbers required for a given scientific study.
We will quantify the benefits of the proposed novel approaches on the basis of clinical observations (animal wound-picking, infection signs, tissue samples), by means of radiological and MR imaging of skull and skin, microbiological assessment of the wound margin samples, and post-mortem histological assessment in animals that have reached the predicted endpoints of their involvement in the neuroscientific study. It will allow for an objective assessment of the benefits that these approaches harbour. We assume that implant integration will be substantially improved in all our animals, thereby benefitting the welfare and health of > 12 animals annually in Newcastle alone.
We assume that these novel approaches will be adopted by a significant number of laboratories in the UK, as the funding for the slightly increased implant costs is likely to be made available, given adequate justification. It may thus benefit a total of ~30-40 animals per year in the UK. The uptake beyond the UK is more difficult to predict, but assuming that >20% of laboratories world- wide adopt the techniques over the course of the next 5-10 years, it may benefit 150 animals in the US alone (based on an overall use of 65000 NHP in the US (2012), of which ~5% may have been involved in neuroscience research (n~=3250). Of these 20% may have been macaques with cranial implants (a rough estimate in the absence of exact numbers; n~=750). Assuming an uptake of 20%, results in 150 animals p.a. benefitting from improved animal welfare (extending over many years for each animal).
Assuming success, we are considering taking the proposed developments further, adapting them to the specific needs of human orthopaedic surgery, whereby the outcomes of this grant will be used to inform these developments. Thus, the outcomes from this grant may prove beneficial to future human exteriorized orthopaedic implant surgery.
We will quantify the benefits of the proposed novel approaches on the basis of clinical observations (animal wound-picking, infection signs, tissue samples), by means of radiological and MR imaging of skull and skin, microbiological assessment of the wound margin samples, and post-mortem histological assessment in animals that have reached the predicted endpoints of their involvement in the neuroscientific study. It will allow for an objective assessment of the benefits that these approaches harbour. We assume that implant integration will be substantially improved in all our animals, thereby benefitting the welfare and health of > 12 animals annually in Newcastle alone.
We assume that these novel approaches will be adopted by a significant number of laboratories in the UK, as the funding for the slightly increased implant costs is likely to be made available, given adequate justification. It may thus benefit a total of ~30-40 animals per year in the UK. The uptake beyond the UK is more difficult to predict, but assuming that >20% of laboratories world- wide adopt the techniques over the course of the next 5-10 years, it may benefit 150 animals in the US alone (based on an overall use of 65000 NHP in the US (2012), of which ~5% may have been involved in neuroscience research (n~=3250). Of these 20% may have been macaques with cranial implants (a rough estimate in the absence of exact numbers; n~=750). Assuming an uptake of 20%, results in 150 animals p.a. benefitting from improved animal welfare (extending over many years for each animal).
Assuming success, we are considering taking the proposed developments further, adapting them to the specific needs of human orthopaedic surgery, whereby the outcomes of this grant will be used to inform these developments. Thus, the outcomes from this grant may prove beneficial to future human exteriorized orthopaedic implant surgery.
